79 results on '"Olga V. Savinova"'
Search Results
2. Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia
- Author
-
Mugdha V. Padalkar, Alexandra H. Tsivitis, Ylona Gelfman, Mariya Kasiyanyk, Neil Kaungumpillil, Danyang Ma, Michael Gao, Kelly A. Borges, Puneet Dhaliwal, Saud Nasruddin, Sruthi Saji, Hina Gilani, Eric J. Schram, Mohnish Singh, Maria M. Plummer, and Olga V. Savinova
- Subjects
triglycerides ,cholesterol ,chronic kidney disease ,mouse model ,atherosclerosis ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundAtherosclerotic cardiovascular disease is prevalent among patients with chronic kidney disease (CKD). In this study, we initially aimed to test whether vascular calcification associated with CKD can worsen atherosclerosis. However, a paradoxical finding emerged from attempting to test this hypothesis in a mouse model of adenine-induced CKD.MethodsWe combined adenine-induced CKD and diet-induced atherosclerosis in mice with a mutation in the low-density lipoprotein receptor gene. In the first study, mice were co-treated with 0.2% adenine in a western diet for 8 weeks to induce CKD and atherosclerosis simultaneously. In the second study, mice were pre-treated with adenine in a regular diet for 8 weeks, followed by a western diet for another 8 weeks.ResultsCo-treatment with adenine and a western diet resulted in a reduction of plasma triglycerides and cholesterol, liver lipid contents, and atherosclerosis in co-treated mice when compared with the western-only group, despite a fully penetrant CKD phenotype developed in response to adenine. In the two-step model, renal tubulointerstitial damage and polyuria persisted after the discontinuation of adenine in the adenine-pre-treated mice. The mice, however, had similar plasma triglycerides, cholesterol, liver lipid contents, and aortic root atherosclerosis after being fed a western diet, irrespective of adenine pre-treatment. Unexpectedly, adenine pre-treated mice consumed twice the calories from the diet as those not pre-treated without showing an increase in body weight.ConclusionThe adenine-induced CKD model does not recapitulate accelerated atherosclerosis, limiting its use in pre-clinical studies. The results indicate that excessive adenine intake impacts lipid metabolism.
- Published
- 2023
- Full Text
- View/download PDF
3. Vitamin K antagonists and cardiovascular calcification: A systematic review and meta-analysis
- Author
-
Nina D. Kosciuszek, Daniel Kalta, Mohnish Singh, and Olga V. Savinova
- Subjects
cardiovascular calcifications ,atherosclerosis ,coronary artery disease ,breast arterial calcifications (BAC) ,peripheral arterial disease (PAD) ,aortic calcification index ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundMany patients treated with Vitamin K antagonists (VKA) for anticoagulation have concomitant vascular or valvular calcification. This meta-analysis aimed to evaluate a hypothesis that vascular and valvular calcification is a side-effect of VKA treatment.MethodsWe conducted a systematic literature search to identify studies that reported vascular or valvular calcification in patients treated with VKA. The associations between VKA use and calcification were analyzed with random-effects inverse variance models and reported as odds ratios (OR) and 95% confidence intervals (95% CI). In addition, univariate meta-regression analyses were utilized to identify any effect moderators.ResultsThirty-five studies were included (45,757 patients; 6,251 VKA users). The median follow-up was 2.3 years [interquartile range (IQR) of 1.2–4.0]; age 66.2 ± 3.6 years (mean ± SD); the majority of participants were males [77% (IQR: 72–95%)]. VKA use was associated with an increased OR for coronary artery calcification [1.21 (1.08, 1.36), p = 0.001], moderated by the duration of treatment [meta-regression coefficient B of 0.08 (0.03, 0.13), p = 0.0005]. Extra-coronary calcification affecting the aorta, carotid artery, breast artery, and arteries of lower extremities, was also increased in VKA treated patients [1.86 (1.43, 2.42), p < 0.00001] and moderated by the author-reported statistical adjustments of the effect estimates [B: −0.63 (−1.19, −0.08), p = 0.016]. The effect of VKA on the aortic valve calcification was significant [3.07 (1.90, 4.96), p < 0.00001]; however, these studies suffered from a high risk of publication bias.ConclusionVascular and valvular calcification are potential side effects of VKA. The clinical significance of these side effects on cardiovascular outcomes deserves further investigation.
- Published
- 2022
- Full Text
- View/download PDF
4. Long-term consumption of artificial sweeteners does not affect cardiovascular health and survival in rats
- Author
-
Satvinder K. Guru, Ying Li, Olga V. Savinova, and Youhua Zhang
- Subjects
Artificial sweeteners ,Blood pressure ,Arterial stiffness ,Cardiac function ,Electrophysiology ,Atrial fibrillation ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Recent epidemiological cohort studies have suggested that consumption of artificial sweeteners (AS) is associated with adverse cardiovascular events and mortality. However, these population association studies cannot establish a causal relationship. In this study we investigated the effect of long-term (1-year) consumption of AS (Equal and Splenda, two commonly used AS) on cardiovascular health and survival in rats. Methods Adult Sprague-Dawley rats (both sexes, 4–5 months old) were randomized into the following 3 groups: control (n = 21), AS Equal (n = 21) and Splenda (n = 18). In the AS groups, Equal or Splenda was added to the drinking water (2-packets/250 ml), while drinking water alone was used in the control rats. The treatment was administered for 12 months. Cardiovascular function and survival were monitored in all animals. Results It was found that rats in the AS groups consistently consumed more sweetened water than those in the control group. AS did not affect body weight, non-fasting blood cholesterol, triglycerides, blood pressure or pulse wave velocity. There were no significant differences in left ventricular wall thicknesses, chamber dimension, cardiac function or survival. AS did not affect heart rate or atrial effective refractory period. However, rats in both Equal and Splenda groups had prolonged PR intervals (63 ± 5ms in Equal, 68 ± 6 ms in Splenda, vs 56 ± 8 ms in control, p
- Published
- 2022
- Full Text
- View/download PDF
5. Effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low‐density lipoproteins in isolated perfused rat livers
- Author
-
Rachel E. Walker, Olga V. Savinova, Theresa L. Pedersen, John W. Newman, and Gregory C. Shearer
- Subjects
compartmental modeling ,fatty acid/metabolism ,lipoproteins ,perfusion ,polyunsaturated fatty acids ,soluble epoxide hydrolase inhibitor ,Physiology ,QP1-981 - Abstract
Abstract Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low‐density lipoproteins (VLDL) contain oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL oxylipins. A compartmental model of deuterium‐labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several oxylipins by a similar amount (13‐HOTrE, 35% [4%,55%], −1.3 nM; 9(10)‐EpODE, 29% [3%,49%], −2.0 nM; 15(16)‐EpODE, 29% [2%,49%], −1.6 nM; AA‐derived diols, 32% [5%,52%], −2.4 nM; 19(20)‐DiHDPA, 31% [7%,50%], −1.0 nM). However, the EPA‐derived epoxide, 17(18)‐EpETE, was decreased by 75% [49%,88%], (−0.52 nM) with LPS, double the suppression of other oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)‐EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL‐oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport.
- Published
- 2021
- Full Text
- View/download PDF
6. Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease
- Author
-
Roman N. Rodionov, Hoshimjon Begmatov, Natalia Jarzebska, Ketul Patel, Matthew T. Mills, Zulaikha Ghani, Doreen Khakshour, Pankti Tamboli, Mitul N. Patel, Mirette Abdalla, Maryann Assaf, Stefan R. Bornstein, Jose Luis Millan, Stefanie M. Bode‐Böger, Jens Martens‐Lobenhoffer, Norbert Weiss, and Olga V. Savinova
- Subjects
cardiac remodeling ,coronary artery disease ,coronary calcium ,homoarginine ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Homoarginine (hArg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hArg can inhibit tissue‐nonspecific alkaline phosphatase (TNAP), an enzyme that promotes vascular calcification. We hypothesized that hArg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low‐density lipoprotein receptor mutation (wicked high cholesterol [WHC] allele). WHC and WHC–endothelial TNAP mice received placebo or hArg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC–endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P
- Published
- 2019
- Full Text
- View/download PDF
7. Marketing analysis of the medical representatives' activity aimed on information support for promoted medications
- Author
-
Elizaveta A. Winter, Tatiana M. Litvinova, Dmitrii V. Babaskin, Liudmila I. Babaskina, and Olga V. Savinova
- Subjects
Environmental sciences ,GE1-350 ,Technological innovations. Automation ,HD45-45.2 - Published
- 2019
- Full Text
- View/download PDF
8. Transgenic Overexpression of Tissue‐Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification
- Author
-
Alexei Y. Savinov, Maryam Salehi, Manisha C. Yadav, Ilian Radichev, José Luis Millán, and Olga V. Savinova
- Subjects
arteriosclerosis ,cardiovascular diseases ,endothelium ,enzymes ,lesion ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Ectopic vascular calcification is a common condition associated with aging, atherosclerosis, diabetes, and/or chronic kidney disease. Smooth muscle cells are the best characterized source of osteogenic progenitors in the vasculature; however, recent studies suggest that cells of endothelial origin can also promote calcification. To test this, we sought to increase the osteogenic potential of endothelial cells by overexpressing tissue‐nonspecific alkaline phosphatase (TNAP), a key enzyme that regulates biomineralization, and to determine the pathophysiological effect of endothelial TNAP on vascular calcification and cardiovascular function. Methods and Results We demonstrated previously that mice transgenic for ALPL (gene encoding human TNAP) develop severe arterial medial calcification and reduced viability when TNAP is overexpressed in smooth muscle cells. In this study, we expressed the ALPL transgene in endothelial cells following endothelial‐specific Tie2‐Cre recombination. Mice with endothelial TNAP overexpression survived well into adulthood and displayed generalized arterial calcification. Genes associated with osteochondrogenesis (Runx2, Bglap, Spp1, Opg, and Col2a1) were upregulated in the aortas of endothelial TNAP animals compared with controls. Lesions in coronary arteries of endothelial TNAP mice showed immunoreactivity to Runx2, osteocalcin, osteopontin, and collagen II as well as increased deposition of sialoproteins revealed by lectin staining. By 23 weeks of age, endothelial TNAP mice developed elevated blood pressure and compensatory left ventricular hypertrophy with preserved ejection fraction. Conclusions This study presented a novel genetic model demonstrating the osteogenic potential of TNAP‐positive endothelial cells in promoting pathophysiological vascular calcification.
- Published
- 2015
- Full Text
- View/download PDF
9. Meta-analysis of the effect of colchicine on C-reactive protein in patients with acute and chronic coronary syndromes
- Author
-
Mustafa Alam, Evangelos Kontopantelis, Mamas A. Mamas, Olga V. Savinova, Amit Jhaveri, Emaad Siddiqui, and Sunny Jhamnani
- Subjects
General Medicine ,Cardiology and Cardiovascular Medicine - Published
- 2023
- Full Text
- View/download PDF
10. Addressing disparities in medicine through medical curriculum change: a student perspective
- Author
-
Amina, Kureshi, Scott, Landman, Meher, Ahmed, Olga V, Savinova, and Diane, Becker
- Subjects
Complementary and Manual Therapy ,Students, Medical ,Education, Medical ,Complementary and alternative medicine ,education ,Humans ,Curriculum ,Cultural Competency ,Schools, Medical - Abstract
Cultural competency training has been a focus of medical schools for some time. An essential step in developing culturally competent physicians, effective cultural competency training has previously been researched at medical schools. Before forming a diversity task force to head cultural competency training, one medical school utilized medical student volunteers to review current teaching material and provide suggestions to increase cultural competency training. A study group consisting of three faculty members and 29 medical students was formed on a voluntary basis during the summer of 2020. Based on medical student opinion and reviewed teaching materials, learning tools were created to guide medical curricular updates. This experience resulted in the formation of four teaching tools: a didactic lecture checklist to include more diverse patient populations; case-based learning objectives that focus on social determinants of health; a facilitator question script to encourage group discussion and student feedback on the given clinical cases; and a student reflection form on the effects of race, gender, and socioeconomic status on patients and medical professionals in the clinical setting. Updating the medical school curriculum is a constant and ongoing process. Forming a diversity task force to guide these changes and regularly review medical teaching materials will help train physicians ready to care for a diverse patient population. In addition, the use of the suggested teaching tools may help guide the review process for such committees at other medical schools.
- Published
- 2022
- Full Text
- View/download PDF
11. Trafficking of nonesterified fatty acids in insulin resistance and relationship to dysglycemia
- Author
-
Michael H. Green, Gregory C. Shearer, William S. Harris, Olga V. Savinova, Rachel E Walker, Jennifer Lynn Ford, and Raymond C. Boston
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Physiology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Fatty Acids, Nonesterified ,Palmitic acid ,chemistry.chemical_compound ,NEFA ,Insulin resistance ,Double-Blind Method ,Physiology (medical) ,Internal medicine ,Insulin Secretion ,medicine ,Humans ,Lipolysis ,Metabolic Syndrome ,chemistry.chemical_classification ,Glucose tolerance test ,medicine.diagnostic_test ,Insulin ,Fatty acid ,Glucose Tolerance Test ,Middle Aged ,medicine.disease ,Lipids ,Hypoglycemia ,Glucose ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Hyperglycemia ,Female ,Insulin Resistance ,Metabolic syndrome ,Research Article - Abstract
In adipose, insulin functions to suppress intracellular lipolysis and secretion of nonesterified fatty acid (NEFA) into plasma. We applied glucose and NEFA minimal models (MM) following a frequently sampled intravenous glucose tolerance test (FSIVGTT) to assess glucose-specific and NEFA-specific insulin resistance. We used total NEFA and individual fatty acids in the NEFA MM, comparing the model parameters in metabolic syndrome (MetSyn) subjects ( n = 52) with optimally healthy controls (OptHC; n = 14). Results are reported as mean difference (95% confidence interval). Using the glucose MM, MetSyn subjects had lower [−73% (−82, −57)] sensitivity to insulin (Si) and higher [138% (44, 293)] acute insulin response to glucose (AIRg). Using the NEFA MM, MetSyn subjects had lower [−24% (−35, −13)] percent suppression, higher [32% (15, 52)] threshold glucose (gs), and a higher [81% (12, 192)] affinity constant altering NEFA secretion (ϕ). Comparing fatty acids, percent suppression was lower in myristic acid (MA) than in all other fatty acids, and the stearic acid (SA) response was so unique that it did not fit the NEFA MM. MA and SA percent of total were increased at 50 min after glucose injection, whereas oleic acid (OA) and palmitic acid (PA) were decreased ( P < 0.05). We conclude that the NEFA MM, as well as the response of individual NEFA fatty acids after a FSIVGTT, differ between OptHC and MetSyn subjects and that the NEFA MM parameters differ between individual fatty acids.
- Published
- 2020
- Full Text
- View/download PDF
12. Abstract 12516: Vascular Calcification Does Not Affect Cardiovascular Structure and Function During the Reversal of Atherosclerosis
- Author
-
Daniel M Kalta, Xin Lin, Mohnish Singh, and Olga V Savinova
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Animal models are used to study the mechanisms of reversal of atherosclerosis. Due to the minimal extent of plaque calcification, commonly used mouse models do not provide good insight into the regression of calcified plaques. To address this question, we developed a mouse strain that is genetically predisposed to atherosclerotic calcification. Hypothesis: The purpose of this study was to compare the effects of the reversal of atherosclerosis on cardiovascular physiology between mice predisposed to calcification and control mice. Methods: All mice (n=35) had a mutation of a low-density lipoprotein receptor and developed atherosclerosis over a course of 15 weeks while on a Western diet. The experimental groups consisted of mice overexpressing TNAP (tissue-nonspecific alkaline phosphatase) in macrophages under the control of LysM-Cre recombinase, and the control littermates. After 23 weeks of age (baseline), mice were switched to a normal diet. Echocardiographic studies were performed to assess cardiac structure and function at baseline and at 52 weeks of age at the completion of the diet reversal protocol. MicroCT analysis of calcification was performed ex vivo . Data were analyzed via 2-way ANOVA to calculate the effect of diet (atherosclerotic baseline vs reversal) while adjusting for sex. Results: Cardiac parameters including left ventricular (LV) mass, LV internal diameter and wall thickness, ejection fraction, fractional shortening, and aortic valve flow velocity were within the normal range and not statistically different between the two genotypes. CT data confirmed an increase in calcium volume in TNAP overexpressor mice compared to controls. Conclusions: Our data suggest that under conditions of the reversal of atherosclerosis, plaque calcification at baseline is not associated with the deterioration of cardiac structure and function in a mouse model.
- Published
- 2021
- Full Text
- View/download PDF
13. Abstract P123: Effects Of Lipid Control On Coronary Calcification
- Author
-
Mustafa Alam and Olga V Savinova
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Introduction: Lipid lowering drugs are some of the most prescribed medications to control coronary artery disease (CAD). The long-term lipid lowering effects on coronary artery calcium (CAC) progression remain a subject of controversy with inconclusive results from multiple literature reviews. The purpose of this meta-analysis is to elucidate the relationship between lipid control and CAC progression. Methods: A computerized search of MEDLINE was conducted using the search terms “coronary”, “calcification”, “statin”, and “lipid lowering.” Search filters included studies in English performed on human subjects, clinical trials, and journal articles. Studies were included if they measured mean value changes from baseline in coronary calcium using cardiac computed tomography. Data were extracted from the articles according to the Cochrane manual. RevMan 5.4 was used to aggregate the studies and report statistics. Results: A total of 13 studies were included with a total of 6671 patients. LDL reduction amongst the studies was significant as compared to placebo or lower dose lipid lowering therapy (standardized mean difference [SMD]: -0.71; 95% CI: -0.79, -0.64; p Conclusion: Lipid lowering therapy shows efficacy in LDL reduction however, it does not lead to coronary calcium reduction. Further studies are needed to elucidate the long-term effects of lipid powering on CAC and the prognostic value of CAC in CAD parents receiving optimal therapy.
- Published
- 2021
- Full Text
- View/download PDF
14. Abstract P129: Ablation Of TNAP (tissue-nonspecific Alkaline Phosphatase) In Macrophages Does Not Affect Atherosclerotic Plaque Calcification Or Cardiovascular Physiology
- Author
-
Ethan Shamsian, Sandy Than, Maria Canellos, Mohnish Singh, and Olga V Savinova
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Introduction: Increased expression of TNAP (tissue-nonspecific alkaline phosphatase) in macrophages exacerbates atherosclerotic calcification in a mouse model. However, whether or not TNAP is necessary in the progression of calcification, or for proper cardiac function has yet been studied. Objective: The purpose of this study was to test the effect of TNAP ablation in macrophages on atherosclerotic plaque calcification and cardiovascular physiology, and compare it to a wild type situation. Methods: Macrophage-specific WHC-mTNAP knockout (KO) mice were produced in our colony by intercrossing floxed alpl transgenic mice ( alpl gene encodes TNAP) and macrophage-specific CRE recombinase mice, in which CRE was expressed under the control of the lysozyme gene promoter. The macrophage TNAP KO strain was developed on the background of homozygous WHC (“wicked high cholesterol”) mutation in the low density lipoprotein receptor gene. WHC-TNAP KO (n=10) and their WHC littermates (n=9) were placed on an atherosclerosis inducing diet at 8 weeks of age. The mice were maintained on the diet for 44 weeks, or until they turned 52 weeks. Microcomputed tomography (microCT) analyses of calcification in the aortic roots and arches were performed ex vivo . Echocardiographic studies were performed to assess cardiac structure and function at 52 weeks of age. Data were analyzed via a 2-way ANOVA to calculate the effect of TNAP ablation on calcification and cardiovascular physiology while adjusting for sex. Results: CT data showed no significant difference in calcification levels between the two genotypes. Cardiac parameters such as left ventricular (LV) mass, LV diameter and wall thickness, ejection fraction, fractional shortening and cardiac output also showed no signifgant difference between the two genotypes. Conclusion: Our data suggest that, despite TNAP expression in macrophages being sufficient to induce calcification of atherosclerotic plaques, it is not necessary in the calcification process. To the extent of our study, the ablation of TNAP in macrophages does not appear to have any consequences in a mouse model of atherosclerosis.
- Published
- 2021
- Full Text
- View/download PDF
15. On the issue of evaluation of safety and efficacy of disinfectants In their examination for the purpose of state registration in the Republic of Belarus
- Author
-
Olga V. Savinova, Ruslan V. Bogdanov, Scientific, and Vadim M. Vasilkevich
- Subjects
State (polity) ,media_common.quotation_subject ,Political science ,Public administration ,The Republic ,media_common - Published
- 2019
- Full Text
- View/download PDF
16. Long‐term Consumption of Artificial Sweeteners Does not Affect Cardiovascular Function but May Cause Cardiac Electrophysiological Abnormalities in Rats
- Author
-
Youhua Zhang, Olga V. Savinova, Satvinder K. Guru, and Ying Li
- Subjects
Consumption (economics) ,business.industry ,Physiology ,Affect (psychology) ,Biochemistry ,Artificial Sweetener ,Term (time) ,Electrophysiology ,Genetics ,Medicine ,business ,Molecular Biology ,Function (biology) ,Biotechnology - Published
- 2021
- Full Text
- View/download PDF
17. Effects of inflammation and soluble epoxide hydrolase inhibition on oxylipin composition of very low‐density lipoproteins in isolated perfused rat livers
- Author
-
Gregory C. Shearer, Rachel E Walker, Theresa L. Pedersen, Olga V. Savinova, and John W. Newman
- Subjects
Lipopolysaccharides ,Male ,Very low-density lipoprotein ,Physiology ,Medical Physiology ,Palmitic Acid ,Adamantane ,fatty acid/metabolism ,Lipoproteins, VLDL ,030204 cardiovascular system & hematology ,lcsh:Physiology ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,0302 clinical medicine ,Enzyme Inhibitors ,Epoxide hydrolase ,chemistry.chemical_classification ,Epoxide Hydrolases ,lcsh:QP1-981 ,Chemistry ,Liver Disease ,Lauric Acids ,soluble epoxide hydrolase inhibitor ,Liver ,Original Article ,lipids (amino acids, peptides, and proteins) ,Chemical and Drug Induced Liver Injury ,VLDL ,Polyunsaturated fatty acid ,compartmental modeling ,polyunsaturated fatty acids ,Epoxide hydrolase 2 ,medicine.medical_specialty ,Linoleic acid ,Clinical Sciences ,In Vitro Techniques ,perfusion ,Linoleic Acid ,03 medical and health sciences ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Oxylipins ,Fatty acid metabolism ,Fatty acid ,Original Articles ,Oxylipin ,Rats ,lipoproteins ,Kinetics ,Endocrinology ,Sprague-Dawley ,fatty acid ,Digestive Diseases ,metabolism ,030217 neurology & neurosurgery - Abstract
Oxylipins are metabolites of polyunsaturated fatty acids that mediate cardiovascular health by attenuation of inflammation, vascular tone, hemostasis, and thrombosis. Very low‐density lipoproteins (VLDL) contain oxylipins, but it is unknown whether the liver regulates their concentrations. In this study, we used a perfused liver model to observe the effect of inflammatory lipopolysaccharide (LPS) challenge and soluble epoxide hydrolase inhibition (sEHi) on VLDL oxylipins. A compartmental model of deuterium‐labeled linoleic acid and palmitic acid incorporation into VLDL was also developed to assess the dependence of VLDL oxylipins on fatty acid incorporation rates. LPS decreased the total fatty acid VLDL content by 30% [6%,47%], and decreased final concentration of several oxylipins by a similar amount (13‐HOTrE, 35% [4%,55%], −1.3 nM; 9(10)‐EpODE, 29% [3%,49%], −2.0 nM; 15(16)‐EpODE, 29% [2%,49%], −1.6 nM; AA‐derived diols, 32% [5%,52%], −2.4 nM; 19(20)‐DiHDPA, 31% [7%,50%], −1.0 nM). However, the EPA‐derived epoxide, 17(18)‐EpETE, was decreased by 75% [49%,88%], (−0.52 nM) with LPS, double the suppression of other oxylipins. sEHi increased final concentration of DHA epoxide, 16(17)‐EpDPE, by 99% [35%,193%], (2.0 nM). Final VLDL‐oxylipin concentrations with LPS treatment were not correlated with linoleic acid kinetics, suggesting they were independently regulated under inflammatory conditions. We conclude that the liver regulates oxylipin incorporation into VLDL, and the oxylipin content is altered by LPS challenge and by inhibition of the epoxide hydrolase pathway. This provides evidence for delivery of systemic oxylipin signals by VLDL transport., Appearance of linoleate label in epoxides (EpOMEs) was greater than for alcohols (HODEs).
- Published
- 2021
18. E-2 | Rotatripsy As A Solution To Heavily Calcified Coronary Lesions: Insights From A Systematic Review
- Author
-
Mustafa Alam, Olga V. Savinova, and Sunny Jhamnani
- Published
- 2022
- Full Text
- View/download PDF
19. ANTICOAGULATION AND VASCULAR CALCIFICATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF VITAMIN K INHIBITORS (VKA)
- Author
-
Nina Kosciuszek, Daniel Kalta, Mohnish Singh, and Olga V. Savinova
- Subjects
Cardiology and Cardiovascular Medicine - Published
- 2022
- Full Text
- View/download PDF
20. Creating 3D Printed Models of a Cadaveric Axillary Vein
- Author
-
Kelsi Hurdle, Olga V. Savinova, Dost Khalique, Shamin F. Islam, Gregory Kurgansky, Avery Gilson, Alexandra Chervonsky, and Jasneel Kahlam
- Subjects
3d printed ,business.industry ,Medicine ,Surgery ,Anatomy ,Cardiology and Cardiovascular Medicine ,Axillary vein ,Cadaveric spasm ,business - Published
- 2021
- Full Text
- View/download PDF
21. Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background
- Author
-
Brian R. Mullen, Sonika Seth, Mussarah Khan, Shannon Moriarty, Elias B. Kampton, Raddy L. Ramos, Anthony W. Esposito, James B. Ackman, Mohammad B. Khan, Yevgeniy Mayr, Faez Siddiqi, Olga V. Savinova, Alyssa R. Toia, John H. Wolfe, Ying Tang, and Joshua A. Cuoco
- Subjects
Male ,0301 basic medicine ,Genetically modified mouse ,C57BL/6 ,Hypoxanthine Phosphoribosyltransferase ,Synaptosomal-Associated Protein 25 ,Mice, Transgenic ,Optogenetics ,Nervous System Malformations ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,biology ,Strain (biology) ,biology.organism_classification ,Receptor, TIE-2 ,Phenotype ,Embryonic stem cell ,Mice, Inbred C57BL ,Luminescent Proteins ,030104 developmental biology ,Animals, Newborn ,Receptors, LDL ,nervous system ,Neurology ,Knockout mouse ,Cerebellar vermis ,Female ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery ,Cerebellar Vermis - Abstract
C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the posterior vermis, indicative of neuronal migration defect during cerebellar development. Recognizing that many genetically engineered (GE) mouse lines are produced from C57BL/6 ES cells or backcrossed to this strain, we performed histological analyses and found that cerebellar heterotopia were a common feature present in the majority of GE lines on this background. Furthermore, we identify GE mouse lines that will be valuable in the study of cerebellar malformations including diverse driver, reporter, and optogenetic lines. Finally, we discuss the implications that these data have on the use of C57BL/6 mice and GE mice on this background in studies of cerebellar development or as models of disease.
- Published
- 2017
- Full Text
- View/download PDF
22. Fluid-Structure Interaction Modeling of Genetically Engineered Micro-calcification at the Luminal Surface of the Aorta in Mice
- Author
-
Dorinamaria Carka, Ian Kelly, and Olga V. Savinova
- Subjects
Stress (mechanics) ,Materials science ,medicine.anatomical_structure ,Endothelium ,Fluid–structure interaction ,Linear elasticity ,Shell (structure) ,medicine ,Shear stress ,Laminar flow ,Composite material ,Viscous stress tensor - Abstract
It is hypothesized that atherosclerosis can be influenced or promoted by early signs of arterial stiffening caused by a polydisperse micron distribution of calcified lesions on the endothelial cell layer. Optical confocal scans (Sensofar S Neox) of open luminal surfaces from mice group with overexpressed tissue-nonspecific alkaline phosphatase in endothelial cells (eTNAP), were treated to optimize resolution and used as geometrical import on a 3D fluid-structure interaction (FSI) finite element model built using COMSOL Multiphysics Software. To investigate shear stress distribution on the endothelium due to the presence of calcified nodules, the aorta was modeled as an idealized cylindrical shell, rigidly attached on the rest of the vessel wall. The calcifications were modeled as linear elastic materials with five times the Young’s modulus of the endothelium, whereas the healthy part of the endothelium was modeled as a hyper elastic material representative of the nonlinear elastic behavior of biological tissue. Due to the small Reynolds number, a fully formed parabolic laminar flow was considered with mean velocity of 17 cm/s. The distribution of the wall shear stress (WSS) magnitude and the disturbed direction of the tangent components of the viscous stress at the fluid-structure interface show a reduction of magnitude by 50% around the calcified nodules. Surface plots of the Mises stress on radial and axial planes, demonstrate a highly non-uniform distribution of deviatoric stress levels and a considerable grading in shear stress transfer from the fluid-structure interface through the thickness of the endothelium.
- Published
- 2020
- Full Text
- View/download PDF
23. A Detailed Explanation of the Distribution of Atherosclerosis in the Pelvic Cavity
- Author
-
Sameer Ahmad Khan, Brian Lee Beatty, and Olga V. Savinova
- Subjects
Physics ,medicine.anatomical_structure ,Distribution (number theory) ,Genetics ,medicine ,Anatomy ,Pelvic cavity ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2019
- Full Text
- View/download PDF
24. Abstract TMP104: Upregulation of Tissue-Nonspecific Alkaline Phosphatase in Endothelial Cells Leads to Intracranial Vascular Calcification: A Useful Model of Primary Familial Brain Calcification
- Author
-
José Luis Millán, Yevgeniy Mayr, Raddy L. Ramos, Elias Kampton, Pranav Singla, Alla Uts, Olga V. Savinova, and Mohammad B. Khan
- Subjects
Advanced and Specialized Nursing ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.disease ,Pathophysiology ,Intracranial vascular ,Downregulation and upregulation ,medicine ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Tissue-nonspecific Alkaline Phosphatase ,Vascular calcification ,Calcification - Abstract
Introduction: Vascular calcification is an important pathophysiological factor contributing to neurodegenerative diseases such as primary familial brain calcification (PFBC) and is a potential therapeutic target. Hypothesis: Given the essential role of tissue-nonspecific alkaline phosphatase (TNAP) in biomineralization, we tested the hypothesis that upregulation of TNAP activity can lead to intracranial calcification. Methods: We previously reported that overexpression of TNAP in endothelial cells (eTNAP) leads to arterial calcification. Here we analyzed intracranial calcification in eTNAP on the original B6;129 and on the C57BL/6 (B6) genetic backgrounds. Histology was performed on formalin-fixed cryo-preserved tissues. Locomotion testing was performed at 23 weeks and analyzed in Matlab. Gene expression was analyzed by qPCR. Results: On the B6;129 background, eTNAP mice developed progressive intracranial calcification (0% were affected at 8 weeks, 71% at 13 weeks, and 100% at 23 weeks, n=7 per group). At 23 weeks, calcification was undetectable in the middle cerebral arteries but was associated with microvasculature in the basal ganglia, thalamus, hindbrain, and cerebellum. Calcified lesions were accompanied by astro- and micro-gliosis. Extravasation of IgG into the brain parenchyma was evident in eTNAP; blood-brain barrier was intact in controls (n=3 per group; 23 weeks). There were no significant differences in the locomotion or behavior (open field exploration) between the eTNAP and controls on the B6;129 background (n=6 per group). On B6 background, eTNAP mice displayed significant motor deficits - reduced ambulation (pRumX2 , Spp1 , SLC17a7 , SLC17a6 of both control and eTNAP mice. Conclusions: Upregulation of TNAP activity can lead to intracranial vascular calcification. Given the similarities in presentation between eTNAP mice and PFBC patients, this model can advance the understanding of PFBC disease progression.
- Published
- 2019
- Full Text
- View/download PDF
25. Abstract TP146: Intracranial Microvascular Calcification: A Cadaveric Study
- Author
-
Maria M. Plummer, Olga V. Savinova, and Daniel J Moussouros
- Subjects
Advanced and Specialized Nursing ,medicine.medical_specialty ,Vascular disease ,business.industry ,Ischemic injury ,medicine.disease ,Brain ischemia ,Internal medicine ,medicine ,Cardiology ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,Cadaveric spasm ,business ,Stroke ,Calcification - Abstract
Introduction: Stroke and brain ischemia are associated with macrovascular calcification. Microvascular calcification may also contribute to cerebrovascular disease, yet its prevalence and pathophysiological significance remain unclear. Hypothesis: Calcification associated with intracranial microvasculature is prevalent in elderly populations and correlates with calcification of proximal macrovascular supply. Methods: Tissues were dissected from 20 cadavers (16 female, 4 male; median age = 81 y; range = 56-94 y) unilaterally on the left side. Three vascular territories were examined representing anterior, middle, and posterior brain regions supplied by distal M4 branches of the middle cerebral artery (MCA). Proximally, two putaminal regions supplied by lenticulostriate arteries (from M1 of the MCA) were examined. Extra- and intracranial internal carotid arteries (ICA) and M1 segments of the MCA from the same subjects were previously scored for calcium; those data were used for correlation analysis. A sensitive and specific calcium detection protocol (alizarin red) was used in all studies alongside H&E. Light microscopy was performed to grade small- (< 20 micron) and large-caliber (20-200 micron) vessels for calcification. Results: Calcification was detected in all subjects, with 95% in small-caliber and 50% in large-caliber microvessels. Non-parametric Spearman correlation analysis revealed significant correlation between calcification of large-caliber microvessels in M4 (but not M1 putaminal vessels) and medial calcification of the MCA (M1 segment; r = 0.6533, p < 0.05). Contrary to our hypothesis, no correlations were found between microvascular calcification and calcification of the ICA. Additionally, no correlations were found between microvascular calcification and atheromatous calcification of either the MCA (M1 segment) or ICA (extra- and intracranial parts). Conclusions: Our study implies that intracranial microvascular calcification is highly prevalent in elderly populations. Additionally, we discovered significant correlation between microvascular calcification and that of the media in mascrovasculature, suggesting a causal link between medial sclerosis and dysfunction of the neurovascular unit.
- Published
- 2019
- Full Text
- View/download PDF
26. Chronic Consumption of a Western Diet causes Perivascular Adipose Tissue (PVAT) Phenotypic Modulation and Increased Macrophages Infiltration
- Author
-
Mohnish Singh, Raddy L. Ramos, Youhua Zhang, Maria Alicia Carrillo Sepulveda, Nicole Maddie, Olga V. Savinova, and Zhongqian Lin
- Subjects
Pathology ,medicine.medical_specialty ,Phenotypic modulation ,Western diet ,Genetics ,medicine ,Adipose tissue ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Infiltration (medical) ,Biotechnology - Published
- 2020
- Full Text
- View/download PDF
27. Abstract 17183: Genetically Engineered Calcification Increases Surface Roughness and Changes the Distribution of Atherosclerotic Plaques in Mice With Atherosclerosis
- Author
-
Anton Mararenko, Ralph Bar-El, Maryann Assaf, Pranav Singla, Ian Kelly, Dorinamaria Carka, Jose Luis Millan, Brian L Beatty, and Olga V Savinova
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: Atherosclerosis is an inflammatory disease that contributes significantly to cardiovascular mortality. Arterial stiffening due to calcification can coexist with or directly influence pathogenesis of atherosclerosis. We hypothesize that arteriosclerosis caused by genetically engineered calcification in mice redistributes shear stress on the endothelial cells, which in turn leads to further accelerated rate of plaque formation. Methods: All of the mice had an LDL receptor mutation and were fed pro-atherogenic diet (1.25% cholesterol). The case group overexpressed tissue-nonspecific alkaline phosphatase in endothelial cells (eTNAP). The luminal surfaces of descending thoracic aorta (TA) and suprarenal abdominal aorta (AA) were scanned using Sensofar S Neox optical confocal microscope at 1 μm vertical resolution. The surface topographies per sample, each measuring 500 x 700 microns, were analyzed for ISO 25178-2 areal roughness parameters using SensoMap. Parameters were compared by t test (n=5 eTNAP, n=6-7 control). Results: We observed a significant difference in the incidence as well as the morphology of the plaques in the eTNAP group compared to control mice. There was a 4.8 fold increase in the number of topological motifs in the thoracic aorta of the eTNAP vs. controls (p < 0.01). Similarly, the number of motifs was increase in the abdominal aorta of the eTNAP mice compared to controls (2.8 fold; p=0.06). The average area of the motifs was significantly larger in the controls compared to the eTNAP group in both segments of the aorta (p=0.06 TA; p < 0.05 AA). The maximum height of the lesions in the TA was not different between the groups (p=0.62), however increased by 74% in the abdominal aorta of the eTNAP compared to controls (p Conclusion: Arteriosclerosis increases surface roughness. In our model, the abdominal region had a high incidence of taller, irregular lesions whereas those in the thoracic aorta were flatter and more spaced. The high resolution scans will be further used to study the hemodynamic disturbances to the endothelial cells using flow dynamics simulations.
- Published
- 2018
- Full Text
- View/download PDF
28. Abstract 384: Differential Effects of Niacin and Omega-3 Fatty Acids on HDL-apolipoprotein A-I Exhange and Cholesterol Efflux Capacity in Subjects with Metabolic Syndrome
- Author
-
Olga V. Savinova, Michael N. Oda, Mark S. Borja, Chongren Tang, William S. Harris, Bradley Hammerson, and Gregory C. Shearer
- Subjects
medicine.medical_specialty ,Apolipoprotein B ,biology ,Chemistry ,Cholesterol ,medicine.disease ,Differential effects ,Omega ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,medicine ,biology.protein ,Efflux ,Metabolic syndrome ,Cardiology and Cardiovascular Medicine ,Niacin - Abstract
Objective: Niacin and omega-3 fatty acids are two therapeutic agents that have been extensively studied for their ability to reduce cardiovascular disease risk, but their effectiveness has more recently been called into question. In this study, we investigate whether these agents alone and in combination alter HDL function, in particular, HDL-apolipoprotein A-I exchange (HAE), a measure of HDL dynamics, and serum cholesterol efflux capacity (CEC). Approach: Fifty-six subjects with metabolic syndrome (MetSyn) were recruited to a double-blind trial and randomized to 16 weeks of treatment with dual placebo, extended release niacin (ERN, 2g/day), prescription omega-3 ethyl esters (P-OM3, 4g/day), or combination. HDL function was assessed at baseline and following 16 weeks of treatment by measuring HAE, macrophage CEC, and ABCA1-specific CEC. Results: Compared to placebo, ERN and P-OM3 alone significantly increased HAE by 15.1 [8.2, 22.0] (pP P =0.002). When evaluated by HAE:apoA-I ratio (a measure of apoA-I specific activity), ERN increased apoA-I specific activity by 20.1% [4.8, 36.9] ( P =0.008), P-OM3 by 30.1% [14.4, 45.9] ( P< 0.0001), however with combination there was no increase, 9% [-6.6, 26.6] ( P =0.34). Triglyceride-adjusted macrophage CEC showed marginally significant increases with P-OM3 therapy ( P =0.05). No therapy significantly improved ABCA1-specific CEC. Conclusions: Much of the effect of ERN on HDL function can be attributed to this therapy raising apoA-I levels, but P-OM3 raises HDL function by independent means, increasing apoA-I specific activity. Future investigation is needed to determine whether interaction between ERN and P-OM3 therapies in combination reduces their overall effectiveness.
- Published
- 2018
- Full Text
- View/download PDF
29. Abstract 456: High Fat Diet-Induced Atherosclerosis-Driven Myocardial Infarction: Role of Cardiac Long Noncoding RNAs in Triiodo-L-Thyronine-Mediated Protection
- Author
-
Anna Domingo, Anthony Martin Gerdes, Jeanwoo Yoo, Clifford Costello, Viswanathan Rajagopalan, Olga V. Savinova, Youhua Zhang, and Emily Schultz
- Subjects
Cardioprotection ,medicine.medical_specialty ,Physiology ,business.industry ,Coronary ligation ,Thyroid ,High fat diet ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Internal medicine ,Thyroid hormones ,Thyronine ,medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Hormone - Abstract
Novel mechanisms associated with therapeutically safe thyroid hormone (TH) therapy are emerging. We have shown that oral triiodo-L-thyronine (T3) offers safe cardioprotection in coronary ligation myocardial infarction (MI), ligation ischemia-reperfusion injury, diabetic cardiomyopathy, etc. via restoration of gene expression. However, safe therapeutic effects following atherosclerosis-driven MI and role of long noncoding RNAs (lncRNAs) is unknown. We employed a mouse model of scavenger receptor B1 knockout with hypomorphic apolipoprotein E. Young adult heterozygote littermates served as controls and all mice received high fat (HF) diet for one month. Along with HF diet, a cohort of homozygotes (HypoE) received therapeutic dose of T3 (5.5 μg/kg/d) in drinking water ad libitum. In HypoE mice, Paigen HF diet induced interstitial fibrotic MI with severe hypertrophic (Heart wt./Body wt., HW/BW: control:4.6±0.14; HypoE:12.9±0.75; p2-fold; p
- Published
- 2017
- Full Text
- View/download PDF
30. Abstract 426: Overexpression of Tissue-nonspecific Alkaline Phosphatase (TNAP) Accelerates Coronary Artery Disease in the Setting of Hypercholesterolemia in Mice
- Author
-
Filippo Romanelli, AnthonyMarco Corbo, Maryam Salehi, Manisha C Yadav, Soha Salman, David Petrosian, Omid J Rashidbaigi, Maria Plummer, Ilian Radichev, Anthony B Pinkerton, José Luis Millán, Alexei Y Savinov, and Olga V Savinova
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Objective: Vascular calcification in asymptomatic individuals is an independent predictor of coronary heart disease (CHD). It is therefore plausible that vascular calcification plays a direct pathophysiological role in atherosclerosis, an underlying cause of CHD. The purpose of this study was to examine the contribution that vascular calcification has on the development of coronary atherosclerosis in a mouse model of familial hypercholesterolemia. Approach and Results: Calcification was induced by overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells of mice harboring a point mutation in the low density lipoprotein receptor ( ldlr, wicked high cholesterol, WHC). Mice were fed an atherogenic diet; echocardiographic and biochemical data were collected longitudinally. Atherosclerosis and vascular calcification were analyzed histologically in the aorta, aortic sinus and coronary arteries. TNAP mice were also treated with a combination of an atherogenic diet and a specific inhibitor of TNAP (SBI-425). Combined with the ldlr mutation and an atherogenic diet, TNAP-driven arterial calcification led to severe atherosclerosis with 100% morbidity characterized by occlusive coronary artery disease, pathological cardiac hypertrophy with dilated LV and reduced ejection fraction (EF). We detected an interaction between vascular calcification and atherosclerosis in mice with endothelial TNAP overexpression. This interaction was particularly prominent in coronary circulation. Targeting TNAP activity therapeutically helped improve survival and heart function of endothelial TNAP overexpressor mice, however the incomplete inhibition of TNAP by SBI-425 was a limitation of this study. Conclusions: Vascular calcification via TNAP overexpression in endothelial cells promotes coronary atherosclerosis and is pathogenic under conditions of hypercholesterolemia.
- Published
- 2017
- Full Text
- View/download PDF
31. Abstract 495: Mouse Model of Mesenteric Ischemia Secondary to Vascular Calcification and Atherosclerosis
- Author
-
Konstantinos Damiris, Filippo Romanelli, Alexei Savinov, José Luis Millan, Jes Kuruvilla, and Olga V Savinova
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Objective: Atherosclerosis is a leading cause of chronic mesenteric ischemia (CMI), defined as intestinal hypoperfusion resulting from stenosis of mesenteric arteries. Symptoms of CMI range from non-specific abdominal pain and weight loss to aversion of food resulting in cachexia. In this study we aim to define intestinal ischemia and its effects on gastrointestinal structure and function in an in vivo model of atherosclerosis. Hypothesis: Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) under conditions of hypercholesterolemia in a mouse model will lead to atherosclerosis causing intestinal ischemia. Methods and Results: We have previously established that endothelial TNAP overexpression (eTNAP) results in calcification of medium-sized arteries including mesenteric. In this study eTNAP was combined with a point mutation in the low-density lipoprotein receptor ( ldlr ^WHC). When fed an atherogenic diet (Paigen’s diet, starting at 8 weeks of age), WHC-eTNAP mice developed acute body weight loss (>15% from baseline), whereas WHC mice continued to gain weight. Examination of the mesenteries of WHC-eTNAP demonstrated eccentric vascular remodeling and stiffening, as well as calcification of atherosclerotic plaques (n=4). Mesenteric arteries of WHC were not affected (n=3). WHC-eTNAP (n=2) mice developed extensive atherosclerosis of submucosal arterioles in the colon where most vessels were narrowed or occluded. Examination of the small intestine in WHC-eTNAP mice showed structurally distressed villi accompanied with an increase in goblet cells and fragmentation of the epithelial layer possibly reflecting cell death. The colon demonstrated loss of goblet cells and signs of denuding of the epithelium. Conclusion: Atherosclerosis induced by overexpression of TNAP causes occlusion of mesenteric arteries as well as structural pathology in the small and large intestine
- Published
- 2017
- Full Text
- View/download PDF
32. Abstract 572: The Effect of Inflammation and Soluble Epoxide Hydrolase Inhibition on Fatty Acid Epoxide Incorporation Into VLDL
- Author
-
Rachel E Walker, Olga V Savinova, Theresa L Pedersen, John W Newman, and Gregory C Shearer
- Subjects
lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine - Abstract
Objective: We have previously observed fatty acid epoxides, a class of potent anti-inflammatory oxylipins, in circulating VLDL. The source of these epoxides is unknown. Cytochrome P450 (CYP450) produces them via oxygenation of polyunsaturated fatty acids (PUFAs), and soluble epoxide hydrolase (sEH) converts them to diols. Our objectives were 1) to investigate if incorporation of epoxides into VLDL occurs via hepatic VLDL synthesis and 2) to determine if incorporation is modulated by inflammation or by inhibition of hepatic sEH. Approach and Results: A 2х2 factorial design was used for treatment assignment. Livers were isolated from rats treated with pro-inflammatory lipopolysaccharide (LPS, 10 mg/kg ip) or saline. AUDA, an inhibitor of sEH (10 μM), was included or excluded in the perfusate (Control, N=3; LPS, N=4; AUDA, N=4; LPS+AUDA, N=4). Livers were perfused for 180 minutes. VLDL was isolated by ultra-centrifugation, then analyzed by LC-MS/MS for oxylipin content. Analyzed epoxides and diols were derived from alpha-linolenic acid (ALA), linoleic acid (LA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Two-way ANOVA’s were used with triglyceride concentration as a covariate. Concentrations (nM) are reported as mean [95% CI]. DHA-derived epoxides increased with AUDA treatment (3.91 [3.01, 5.07]) compared to livers without AUDA (2.06 [1.58, 2.67]) (p=0.004), but other epoxides were unchanged by AUDA. EPA and ALA-derived epoxides decreased with LPS treatment (0.32 [0.22, 0.47]; 2.44 [2.07, 2.87]) compared to animals without LPS (0.73 [0.46, 1.16]; 3.28 [2.71, 3.96]) (p=0.01; 0.02). AA and DHA-derived diols decreased with LPS treatment (1.01 [0.82, 1.25]; 0.21 [0.17, 0.26]) compared to animals without LPS (1.46 [1.15, 1.86]; 0.31 [0.24, 0.39]) (p=0.03; 0.03). Conclusions: Treatment with LPS and AUDA have significant effects on incorporation of epoxides and diols into VLDL, supporting hepatic incorporation controlled by inflammation. Inflammation decreased select EPA- and ALA-derived epoxides. In contrast, sEH inhibition increased only DHA-derived epoxides. Surprisingly, in VLDL only epoxides derived from omega-3 fatty acids were affected by either inflammation or inhibition of sEH.
- Published
- 2017
- Full Text
- View/download PDF
33. Modified Low-Dose Triiodo-L-thyronine Therapy Safely Improves Function Following Myocardial Ischemia-Reperfusion Injury
- Author
-
Olga V. Savinova, Youhua Zhang, Clifford Costello, Viswanathan Rajagopalan, Ann Lehto, Yue-Feng Chen, Samantha Seitter, Christine J. Pol, and A. Martin Gerdes
- Subjects
0301 basic medicine ,Physiology ,ischemia-reperfusion injury ,Infarction ,030204 cardiovascular system & hematology ,Muscle hypertrophy ,Contractility ,03 medical and health sciences ,0302 clinical medicine ,Bolus (medicine) ,Left coronary artery ,heart function ,Physiology (medical) ,Diabetic cardiomyopathy ,medicine.artery ,Medicine ,Original Research ,thyroid hormones ,cardiac physiology ,business.industry ,medicine.disease ,3. Good health ,030104 developmental biology ,Blood pressure ,Anesthesia ,business ,Reperfusion injury ,therapeutic protocol - Abstract
Background: We have shown that thyroid hormones (THs) are cardioprotective and can be potentially used as safe therapeutic agents for diabetic cardiomyopathy and permanent infarction. However, no reliable, clinically translatable protocol exists for TH treatment of myocardial ischemia-reperfusion (IR) injury. We hypothesized that modified low-dose triiodo-L-thyronine (T3) therapy would confer safe therapeutic benefits against IR injury. Methods: Adult female rats underwent left coronary artery ligation for 60 minutes or sham surgeries. At 2 months following surgery and T3 treatment (described below), the rats were subjected to functional, morphological, and molecular examination. Results: Following surgery, the rats were treated with T3 (8 μg/kg/day) or vehicle in drinking water ad libitum following IR for 2 months. Oral T3 significantly improved left ventricular (LV) contractility, relaxation, and relaxation time constant, and decreased beta-myosin heavy chain gene expression. As it takes rats ~6 hours post-surgery to begin drinking water, we then investigated whether modified T3 dosing initiated immediately upon reperfusion confers additional improvement. We injected an intraperitoneal bolus of T3 (12 μg/kg) upon reperfusion, along with low-dose oral T3 (4.5 μg/kg/day) in drinking water for 2 months. Continuous T3 therapy (bolus + low-dose oral) enhanced LV contractility compared with oral T3 alone. Relaxation parameters were also improved compared to vehicle. Importantly, these were accomplished without significant increases in hypertrophy, serum free T3 levels or blood pressure. Conclusions: This is the first study to provide a safe cardiac therapeutic window and optimized, clinically translatable treatment-monitoring protocol for myocardial IR using commercially available and inexpensive T3. Low-dose oral T3 therapy supplemented with bolus treatment initiated upon reperfusion is safer and more efficacious.
- Published
- 2017
34. Restoration of Cardiac Tissue Thyroid Hormone Status in Experimental Hypothyroidism: A Dose-Response Study in Female Rats
- Author
-
Alessandro Saba, Evelyn H. Schlenker, A. Martin Gerdes, Nathan Y. Weltman, Christine J. Pol, Kaie Ojamaa, Olga V. Savinova, Riccardo Zucchi, Daria Colligiani, and Yue-Feng Chen
- Subjects
Cardiac function curve ,Thyroid Hormones ,medicine.medical_specialty ,Rats, Sprague-Dawley ,Endocrinology ,Atrophy ,Hypothyroidism ,In vivo ,Internal medicine ,medicine ,Animals ,Euthyroid ,Thyroid-TRH-TSH ,Fetus ,business.industry ,Myocardium ,Thyroid ,Heart ,Transporter ,medicine.disease ,Rats ,Disease Models, Animal ,Thyroxine ,medicine.anatomical_structure ,cardiovascular system ,Triiodothyronine ,Female ,business ,Hormone - Abstract
Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T3 (instead of T4) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T3 dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T3 and T4 levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T3 led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T3 levels was not associated with restoration of cardiac tissue T3 levels or cardiac function. In fact, a 3-fold higher T3 dosage was necessary to normalize cardiac tissue T3 levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states.
- Published
- 2013
- Full Text
- View/download PDF
35. Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells accelerates coronary artery disease in a mouse model of familial hypercholesterolemia
- Author
-
Jesse Chait, Maryam Salehi, Alexei Y. Savinov, Omid J. Rashidbaigi, Olga V. Savinova, Filippo Romanelli, Manisha C. Yadav, Soha Salman, Kenneth B. Margulies, A. Martin Gerdes, David Petrosian, Jes Kuruvilla, AnthonyMarco Corbo, Maria M. Plummer, José Luis Millán, Ilian A. Radichev, and Anthony B. Pinkerton
- Subjects
0301 basic medicine ,Physiology ,lcsh:Medicine ,Alizarin Staining ,Core Binding Factor Alpha 1 Subunit ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Vascular Medicine ,Biochemistry ,Ventricular Function, Left ,Coronary artery disease ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Medicine and Health Sciences ,Group-Specific Staining ,Enzyme Inhibitors ,lcsh:Science ,Coronary Arteries ,Cells, Cultured ,Staining ,Multidisciplinary ,Arteries ,Animal Models ,Lipids ,Coronary Vessels ,Immunohistochemistry ,3. Good health ,Arterial calcification ,medicine.anatomical_structure ,Experimental Organism Systems ,Echocardiography ,Alkaline phosphatase ,Cytokines ,Anatomy ,Research Article ,medicine.medical_specialty ,Endothelium ,Mouse Models ,Mice, Transgenic ,Biology ,Research and Analysis Methods ,Calcification ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Model Organisms ,Calcification, Physiologic ,Internal medicine ,medicine ,Oil Red O ,Animals ,Humans ,Coronary atherosclerosis ,Nutrition ,Myocardium ,Hematoxylin Staining ,Body Weight ,lcsh:R ,Biology and Life Sciences ,Endothelial Cells ,medicine.disease ,Atherosclerosis ,Alkaline Phosphatase ,Placebo Effect ,Diet ,Coronary arteries ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Receptors, LDL ,Specimen Preparation and Treatment ,Cardiovascular Anatomy ,Blood Vessels ,Diet, Atherogenic ,lcsh:Q ,Endothelium, Vascular ,Physiological Processes ,Blood Chemical Analysis - Abstract
Objective Overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in endothelium leads to arterial calcification in mice. The purpose of this study was to examine the effect of elevated endothelial TNAP on coronary atherosclerosis. In addition, we aimed to examine endogenous TNAP activity in human myocardium. Approach and results A vascular pattern of TNAP activity was observed in human non-failing, ischemic, and idiopathic dilated hearts (5 per group); no differences were noted between groups in this study. Endothelial overexpression of TNAP was achieved in mice harboring a homozygous recessive mutation in the low density lipoprotein receptor (whc allele) utilizing a Tie2-cre recombinase (WHC-eTNAP mice). WHC-eTNAP developed significant coronary artery calcification at baseline compared WHC controls (4312 vs 0μm2 alizarin red area, p
- Published
- 2017
36. Abstract 462: Transgenic Overexpression of Tissue-nonspecific Alkaline Phosphatase in Monocytes/Macrophages Induces Calcification of Atherosclerotic Plaques
- Author
-
Alexei Y. Savinov, Eduard I. Dedkov, Yuan Huang, Olga V. Savinova, Filippo Romanelli, José Luis Millán, and Anthony Marco Corbo
- Subjects
Pathology ,medicine.medical_specialty ,Transgene ,Monocyte ,Cre recombinase ,Inflammation ,Biology ,medicine.disease ,medicine.anatomical_structure ,Downregulation and upregulation ,medicine ,Alkaline phosphatase ,Macrophage ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Calcification - Abstract
Introduction: Calcification of atherosclerotic plaques is associated with different histopathological and clinical manifestations. Microcalcification promotes inflammation and increases plaque instability, whereas macrocalcification is associated with stable fibroatheroma. The mechanisms of initiation and progression of calcification in atherosclerosis are not completely understood. Hypothesis: Upregulation of tissue-nonspecific alkaline phosphatase (TNAP) in monocytes/macrophages can lead to calcification of atherosclerotic plaques in a mouse model. Methods: TNAP overexpression was induced from a targeted transgene in Hprt locus utilizing Cre recombinase driven by monocyte-specific LyzM gene promoter. Resultant mice overexpressing TNAP in cells of monocyte/macrophage lineage (TNAP-Tg) were bred with animals bearing low density lipoprotein receptor mutation. Hypercholesterolemia was induced by feeding Paigen diet for ten weeks. Average plaque area and calcification (area %) were determined from histological sections of the aortic root (5-10 sections/sample). Blood flow velocity in the ascending aorta and left ventricular function were assessed by echocardiography. Results: In the absence of atherosclerosis, no appreciable soft tissue calcification was observed in TNAP-Tg animals (n=2). During progression of atherosclerosis, calcification was detected in the aortic root lesions of TNAP-Tg mice (4.85% of total plaque area) in significant excess compared to controls (0.02%, p Conclusions: We developed an animal model in which the interaction between early calcium deposition inside atherosclerotic lesions and the stability of such lesions can be studied experimentally.
- Published
- 2016
- Full Text
- View/download PDF
37. Thyroid hormone induces sprouting angiogenesis in adult heart of hypothyroid mice through the PDGF-Akt pathway
- Author
-
Olga V. Savinova, Vijaya B. Nareddy, Steven B. Ortmeier, A. Martin Gerdes, Jinghai Chen, Dajun Wang, and April J. Beyer
- Subjects
Platelet-derived growth factor ,Angiogenesis ,medicine.medical_treatment ,Becaplermin ,030204 cardiovascular system & hematology ,Tissue Culture Techniques ,Neovascularization ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,pericyte ,Platelet-Derived Growth Factor ,2. Zero hunger ,0303 health sciences ,biology ,Age Factors ,Heart ,Proto-Oncogene Proteins c-sis ,PDGF ,Coronary Vessels ,cardiovascular system ,Triiodothyronine ,Molecular Medicine ,Female ,medicine.symptom ,Angiogenesis Inducing Agents ,hormones, hormone substitutes, and hormone antagonists ,Platelet-derived growth factor receptor ,Signal Transduction ,endocrine system ,medicine.medical_specialty ,Heart Ventricles ,Neovascularization, Physiologic ,Receptor, Platelet-Derived Growth Factor beta ,03 medical and health sciences ,Hypothyroidism ,Internal medicine ,medicine ,Animals ,sprouting angiogenesis ,Protein kinase B ,030304 developmental biology ,Sprouting angiogenesis ,Myocardium ,Akt ,Growth factor ,Original Articles ,Cell Biology ,thyroid hormone ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Propylthiouracil ,biology.protein ,Proto-Oncogene Proteins c-akt - Abstract
Study of physiological angiogenesis and associated signalling mechanisms in adult heart has been limited by the lack of a robust animal model. We investigated thyroid hormone-induced sprouting angiogenesis and the underlying mechanism. Hypothyroidism was induced in C57BL/6J mice by feeding with propylthiouracil (PTU). One year of PTU treatment induced heart failure. Both 12 weeks- (young) and 1 year-PTU (middle age) treatment caused a remarkable capillary rarefaction observed in capillary density. Three-day Triiodothyronine (T3) treatment significantly induced cardiac capillary growth in hypothyroid mice. In cultured left ventricle (LV) tissues from PTU-treated mice, T3 also induced robust sprouting angiogenesis where pericyte-wrapped endothelial cells formed tubes. The in vitro T3 angiogenic response was similar in mice pre-treated with PTU for periods ranging from 1.5 to 12 months. Besides bFGF and VEGF(164) , PDGF-BB was the most robust angiogenic growth factor, which stimulated notable sprouting angiogenesis in cultured hypothyroid LV tissues with increasing potency, but had little effect on tissues from euthyroid mice. T3 treatment significantly increased PDGF receptor beta (PDGFR-β) protein levels in hypothyroid heart. PDGFR inhibitors blocked the action of T3 both on sprouting angiogenesis in cultured LV tissue and on capillary growth in vivo. In addition, activation of Akt signalling mediated in T3-induced angiogenesis was blocked by PDGFR inhibitor and neutralizing antibody. Our results suggest that hypothyroidism leads to cardiac microvascular impairment and rarefaction with increased sensitivity to angiogenic growth factors. T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt.
- Published
- 2012
- Full Text
- View/download PDF
38. Fish oil — How does it reduce plasma triglycerides?
- Author
-
Gregory C. Shearer, Olga V. Savinova, and William S. Harris
- Subjects
medicine.medical_specialty ,Very low-density lipoprotein ,Lipolysis ,Adipose tissue ,Hormone-sensitive lipase ,Fatty Acids, Nonesterified ,Lipoproteins, VLDL ,Biology ,Article ,chemistry.chemical_compound ,Fish Oils ,Chylomicron remnant ,Adipocyte ,Internal medicine ,Fatty Acids, Omega-3 ,Adipocytes ,medicine ,Humans ,Molecular Biology ,Triglycerides ,Lipoprotein lipase ,Cell Biology ,Sterol Esterase ,Endocrinology ,Liver ,chemistry ,Organ Specificity ,Lipogenesis ,Insulin Resistance - Abstract
Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels. At the pharmaceutical dose, 3.4g/day, they reduce plasma TG by about 25-50% after one month of treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
- Published
- 2012
- Full Text
- View/download PDF
39. 1088 - Overexpression of Tissue-Nonspecific Alkaline Phosphatase (Tnap) in a Mouse Model of Atherosclerosis Leads to Adhesions and Ischemic Injury to the Intestine
- Author
-
Benjamin Kuhar, Olga V. Savinova, Konstantinos Damiris, Maria M. Plummer, José Luis Millán, Daniel J Moussouros, Lawrence Markel, Amira Moussa, Afshan Tabassum, Matthew A. Cascio, Jes Kuruvilla, Slava Gitelman, JoseYnigo Villanueva, Ashna Mehra, Jennifer Behbodikhah, Alexander Ogden, Muhddesa Lakhana, Gregg D. Blumberg, and Muhammad Ahsan
- Subjects
Pathology ,medicine.medical_specialty ,Hepatology ,Chemistry ,Gastroenterology ,medicine ,Ischemic injury ,Tissue-nonspecific Alkaline Phosphatase - Published
- 2018
- Full Text
- View/download PDF
40. The Nfkb1 and Nfkb2 Proteins p105 and p100 Function as the Core of High-Molecular-Weight Heterogeneous Complexes
- Author
-
Olga V. Savinova, Alexander Hoffmann, and Gourisankar Ghosh
- Subjects
Models, Molecular ,genetic structures ,Dimer ,Protein subunit ,Molecular Sequence Data ,Sequence alignment ,Biology ,Article ,Cell Line ,chemistry.chemical_compound ,NF-kappa B p52 Subunit ,Humans ,Amino Acid Sequence ,Protein Precursors ,Binding site ,Peptide sequence ,Molecular Biology ,Binding Sites ,NF-kappa B ,NF-kappa B p50 Subunit ,Cell Biology ,Protein Structure, Tertiary ,Protein Subunits ,chemistry ,Biochemistry ,Cytoplasm ,Ankyrin repeat ,Dimerization ,Sequence Alignment - Abstract
Nfkb1 and Nfkb2 proteins p105 and p100 serve both as NF-kappaB precursors and inhibitors of NF-kappaB dimers. In a biochemical characterization of endogenous cytoplasmic and purified recombinant proteins, we found that p105 and p100 assemble into high-molecular-weight complexes that contribute to the regulation of all NF-kappaB isoforms. Unlike the classical inhibitors IkappaBalpha, -beta, and -epsilon, high-molecular-weight complexes of p105 and p100 proteins bind NF-kappaB subunits in two modes: through direct dimerization of Rel homology domain-containing NF-kappaB polypeptides and through interactions of the p105 and p100 ankyrin repeats with preformed NF-kappaB dimers, thereby mediating the bona fide IkappaB activities, IkappaBgamma and IkappaBdelta. Our biochemical evidence suggests an assembly pathway in which kinetic mechanisms control NF-kappaB dimer formation via processing and assembly of large complexes that contain IkappaB activities.
- Published
- 2009
- Full Text
- View/download PDF
41. Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis
- Author
-
Olga V. Savinova, Richard S. Smith, Jeffrey K. Marchant, Simon W. M. John, and Douglas B. Gould
- Subjects
Collagen Type IV ,Pathology ,medicine.medical_specialty ,Eye Diseases ,genetic structures ,Mutant ,Biology ,Endoplasmic Reticulum ,Basement Membrane ,Pathogenesis ,Mice ,Dysgenesis ,Type IV collagen ,Microscopy, Electron, Transmission ,Anterior Eye Segment ,Genetics ,medicine ,Animals ,Molecular Biology ,Genetics (clinical) ,Mice, Knockout ,Optic nerve hypoplasia ,Endoplasmic reticulum ,Optic Nerve ,General Medicine ,Anatomy ,medicine.disease ,Immunohistochemistry ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Retinal ganglion cell ,Mutation ,Optic nerve - Abstract
Ocular anterior segment dysgenesis (ASD) is a complex and poorly understood group of conditions. A large proportion of individuals with ASD develop glaucoma, a leading cause of blindness resulting from retinal ganglion cell death. Optic nerve hypoplasia is thought to have distinct causes and is a leading cause of blindness in children. Here, we show that a mutation in the type IV collagen alpha 1 (Col4a1) gene can cause both ASD and optic nerve hypoplasia. COL4A1 is a major component of almost all basement membranes. The mutation results in non-secretion of the mutant COL4A1 proteins, which instead accumulate within cells. Basement membrane abnormalities may, therefore, contribute to the phenotype. The mutation also induces endoplasmic reticulum stress and so intracellular stress may contribute to pathogenesis. The overall consequence of the Col4a1 mutation depends on genetic context. In one genetic context, the mutation causes severe ASD with intraocular pressure abnormalities and optic nerve hypoplasia. In a different genetic context, both the ASD and optic nerve hypoplasia are rescued, and we have identified a single dominant locus that confers the phenotypic modification.
- Published
- 2007
- Full Text
- View/download PDF
42. Transgenic Overexpression of Tissue‐Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification
- Author
-
Manisha C. Yadav, Ilian A. Radichev, José Luis Millán, Alexei Y. Savinov, Olga V. Savinova, and Maryam Salehi
- Subjects
Male ,Pathology ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Gene Expression ,030204 cardiovascular system & hematology ,Vascular Medicine ,Generalized arterial calcification ,Mice ,0302 clinical medicine ,Genetically Altered and Transgenic Models ,Osteopontin ,Original Research ,0303 health sciences ,biology ,Calcinosis ,ALPL ,medicine.anatomical_structure ,Endothelium/Vascular Type/Nitric Oxide ,Osteocalcin ,Alkaline phosphatase ,Female ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Endothelium ,endothelium ,enzymes ,Mice, Transgenic ,Real-Time Polymerase Chain Reaction ,lesion ,Peripheral Arterial Disease ,03 medical and health sciences ,Internal medicine ,Genetic model ,medicine ,Animals ,030304 developmental biology ,arteriosclerosis ,business.industry ,Alkaline Phosphatase ,medicine.disease ,cardiovascular diseases ,Endocrinology ,Animal Models of Human Disease ,High Blood Pressure ,lcsh:RC666-701 ,biology.protein ,Endothelium, Vascular ,business ,Basic Science Research ,Calcification - Abstract
Background Ectopic vascular calcification is a common condition associated with aging, atherosclerosis, diabetes, and/or chronic kidney disease. Smooth muscle cells are the best characterized source of osteogenic progenitors in the vasculature; however, recent studies suggest that cells of endothelial origin can also promote calcification. To test this, we sought to increase the osteogenic potential of endothelial cells by overexpressing tissue‐nonspecific alkaline phosphatase ( TNAP ), a key enzyme that regulates biomineralization, and to determine the pathophysiological effect of endothelial TNAP on vascular calcification and cardiovascular function. Methods and Results We demonstrated previously that mice transgenic for ALPL (gene encoding human TNAP ) develop severe arterial medial calcification and reduced viability when TNAP is overexpressed in smooth muscle cells. In this study, we expressed the ALPL transgene in endothelial cells following endothelial‐specific Tie2‐Cre recombination. Mice with endothelial TNAP overexpression survived well into adulthood and displayed generalized arterial calcification. Genes associated with osteochondrogenesis ( Runx2, Bglap, Spp1, Opg, and Col2a1 ) were upregulated in the aortas of endothelial TNAP animals compared with controls. Lesions in coronary arteries of endothelial TNAP mice showed immunoreactivity to Runx2, osteocalcin, osteopontin, and collagen II as well as increased deposition of sialoproteins revealed by lectin staining. By 23 weeks of age, endothelial TNAP mice developed elevated blood pressure and compensatory left ventricular hypertrophy with preserved ejection fraction. Conclusions This study presented a novel genetic model demonstrating the osteogenic potential of TNAP ‐positive endothelial cells in promoting pathophysiological vascular calcification.
- Published
- 2015
43. Abstract 375: Alkaline Phosphatase-driven Vascular Calcification Interacts with Hypercholesterolemia and Leads to Severe Coronary Atherosclerosis and Heart Failure in Mice
- Author
-
Alexei Y Savinov, Manisha C Yadav, José Luis Millán, and Olga V Savinova
- Subjects
Cardiology and Cardiovascular Medicine - Abstract
Objective: Asymptomatic calcification of coronary arteries can independently predict future coronary heart disease. It is not yet clear, however, whether the temporal presence of calcification in coronary arteries is pathogenic. We have recently demonstrated that upregulation of tissue-nonspecific alkaline phosphatase (TNAP) in vascular smooth muscle cells in vivo is sufficient to induce medial calcification. The purpose of this study was to test the hypothesis that TNAP-driven intimal calcification can promote coronary atherosclerosis in a mouse model. Methods: TNAP was overexpressed in endothelial cells in wild type mice and in mice harboring “wicked high cholesterol” (WHC) mutation in the low density lipoprotein receptor. Hypercholesterolemia was induced in WHC mice by feeding an atherogenic diet. Physiological, histological, and biochemical data were collected longitudinally. Results: In the absence of hypercholesterolemia, pan-endothelial overexpression of TNAP induced systemic generalized arterial calcification with normal calcium and phosphate metabolism, but with elevated blood pressure and physiological left ventricular (LV) hypertrophy. Calcific nodules first appear in the arterial intima and expand into the arterial media. Combined with the WHC mutation and 6-8 weeks on atherogenic diet, TNAP-driven arterial calcification led to severe atherosclerosis with 100% morbidity characterized by occlusive coronary artery disease (histologically), pathological cardiac hypertrophy with LV dilation, and reduced cardiac ejection fraction (EF). Conclusions: Arterial calcification promotes lipid deposition and is pathogenic when cholesterol is elevated due to genetic and dietary causes.
- Published
- 2015
- Full Text
- View/download PDF
44. Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration
- Author
-
Simon W. M. John, Zachary H. Robinson, Amy Snow, Olga V. Savinova, Iok-Hou Pang, Lawriston A. Wilson, Michael G. Anderson, I. Mihai Cosma, Richard T. Libby, Richard S. Smith, and Abbot F. Clark
- Subjects
Retinal Ganglion Cells ,Intraocular pressure ,medicine.medical_specialty ,genetic structures ,Anterior Chamber ,Physiology ,Eye disease ,Iris ,Glaucoma ,Eye ,Retinal ganglion ,Optic neuropathy ,Mice ,Ophthalmology ,medicine ,Animals ,Intraocular Pressure ,business.industry ,Neurodegeneration ,Optic Nerve ,DNA ,medicine.disease ,eye diseases ,Sensory Systems ,medicine.anatomical_structure ,Retinal ganglion cell ,Mice, Inbred DBA ,Nerve Degeneration ,Disease Progression ,Optic nerve ,sense organs ,business ,Neuroscience - Abstract
The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.
- Published
- 2005
- Full Text
- View/download PDF
45. Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma
- Author
-
Simon W. M. John, Richard S. Smith, Douglas B. Gould, Mario Torrado, Laura Miceli-Libby, Olga V. Savinova, and Stanislav I. Tomarev
- Subjects
Adult ,Retinal Ganglion Cells ,Genetically modified mouse ,Intraocular pressure ,genetic structures ,Transgene ,Glaucoma ,Mice, Transgenic ,Biology ,Eye ,Bioinformatics ,Abnormal protein ,Mice ,Adrenal Cortex Hormones ,Trabecular Meshwork ,medicine ,Animals ,Humans ,Eye Proteins ,Promoter Regions, Genetic ,Cell Growth and Development ,Molecular Biology ,Intraocular Pressure ,Glycoproteins ,Regulation of gene expression ,Optic Nerve ,Cell Biology ,medicine.disease ,eye diseases ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,medicine.anatomical_structure ,Gene Expression Regulation ,Optic nerve ,sense organs ,Trabecular meshwork ,Glaucoma, Open-Angle - Abstract
Despite the importance of MYOC for glaucoma, the protein's normal function(s) and the pathogenic mechanism(s) of MYOC mutations are not clear. Elevated intraocular pressure (IOP) and glaucoma are sometimes induced by corticosteroids, and corticosteroid use can result in substantially increased MYOC expression. It has been suggested, therefore, that steroid-induced MYOC protein levels cause steroid-induced glaucoma and that protein level-increasing mutations in MYOC contribute to glaucoma not associated with steroid use. A causative role of elevated MYOC levels in steroid-induced glaucoma is controversial, however, and it is not clear if elevated MYOC levels can result in IOP elevation. To directly test if increased levels of MYOC can cause IOP elevation and glaucoma, we generated bacterial artificial chromosome transgenic mice that overexpress Myoc at a level similar to that induced by corticosteroid use. These mice do not develop elevated IOP or glaucoma. Our present findings, along with the absence of glaucoma in mice completely lacking MYOC, show that changing the level of MYOC is not pathogenic (from absent to approximately 15 times normal). These findings suggest that noncoding sequence variants are unlikely to influence glaucoma and that disease pathogenesis in primary open-angle glaucoma patients is dependent upon the expression of abnormal mutant proteins. This work does not support a causative role for increased MYOC levels or the MYOC gene in steroid-induced glaucoma.
- Published
- 2004
- Full Text
- View/download PDF
46. By Altering Ocular Immune Privilege, Bone Marrow–derived Cells Pathogenically Contribute to DBA/2J Pigmentary Glaucoma
- Author
-
Bruce R. Ksander, Olga V. Savinova, Meredith S. Gregory, Simon W. M. John, Jun-Song Mo, David V. Serreze, J. Wayne Streilein, Michael G. Anderson, and Richard S. Smith
- Subjects
immune tolerance ,anterior chamber ,Pathology ,medicine.medical_specialty ,genetic structures ,leukocytes ,T cell ,Immunology ,Iris ,Bone Marrow Cells ,Inflammation ,delayed hypersensitivity ,Biology ,Eye ,Article ,Immune tolerance ,Aqueous Humor ,Mice ,Immune system ,Immune reconstitution inflammatory syndrome ,Immune privilege ,Cell Movement ,medicine ,Animals ,Immunology and Allergy ,fas Receptor ,Mice, Inbred BALB C ,medicine.disease ,eye diseases ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Mice, Inbred DBA ,inflammation ,Pigment dispersion syndrome ,Female ,sense organs ,Bone marrow ,medicine.symptom ,Retinal Pigments ,Glaucoma, Open-Angle - Abstract
Pigment dispersion syndrome causes iris pigment release and often progresses to elevated intraocular pressure and pigmentary glaucoma (PG). Because melanin pigment can have adjuvant like properties and because the Gpnmb gene, which contributes to pigment dispersion in DBA/2J (D2) mice, is expressed in dendritic cells, we tested the hypothesis that ocular immune abnormalities participate in PG phenotypes. Strikingly, we show that D2 eyes exhibit defects of the normally immunosuppressive ocular microenvironment including inability of aqueous humor to inhibit T cell activation, failure to support anterior chamber (AC)-associated immune deviation, and loss of ocular immune privilege. Histologic analysis demonstrates infiltration of inflammatory leukocytes into the AC and their accumulation within the iris, whereas clinical indications of inflammation are typically very mild to undetectable. Importantly, some of these abnormalities precede clinical indications of pigment dispersal, suggesting an early role in disease etiology. Using bone marrow chimeras, we show that lymphohematopoietic cell lineages largely dictate the progression of pigment dispersion, the ability of the eye to support induction of AC-associated immune deviation, and the integrity of the blood/ocular barrier. These results suggest previously unsuspected roles for bone marrow–derived cells and ocular immune privilege in the pathogenesis of PG.
- Published
- 2003
- Full Text
- View/download PDF
47. Apolipoprotein A-I exchange is impaired in metabolic syndrome patients asymptomatic for diabetes and cardiovascular disease
- Author
-
Michael N. Oda, Gregory C. Shearer, Bradley Hammerson, Mark S. Borja, Chongren Tang, and Olga V. Savinova
- Subjects
Male ,0301 basic medicine ,Apolipoprotein B ,Physiology ,lcsh:Medicine ,Cardiovascular Medicine ,030204 cardiovascular system & hematology ,Biochemistry ,Gastroenterology ,chemistry.chemical_compound ,Mathematical and Statistical Techniques ,Endocrinology ,0302 clinical medicine ,Medicine and Health Sciences ,Medicine ,lcsh:Science ,Metabolic Syndrome ,Multidisciplinary ,biology ,Reverse cholesterol transport ,Drugs ,Middle Aged ,Lipids ,Body Fluids ,3. Good health ,Protein Transport ,Cholesterol ,Blood ,Cardiovascular Diseases ,Physical Sciences ,cardiovascular system ,Regression Analysis ,Female ,lipids (amino acids, peptides, and proteins) ,Anatomy ,medicine.symptom ,Lipoproteins, HDL ,Statistics (Mathematics) ,ATP Binding Cassette Transporter 1 ,Research Article ,Adult ,medicine.medical_specialty ,Endocrine Disorders ,Lipoproteins ,Linear Regression Analysis ,Research and Analysis Methods ,Asymptomatic ,Blood Plasma ,03 medical and health sciences ,Diabetes mellitus ,Internal medicine ,Diabetes Mellitus ,Humans ,Statistical Methods ,Pharmacology ,Apolipoprotein A-I ,Triglyceride ,business.industry ,lcsh:R ,Statins ,Biology and Life Sciences ,Proteins ,medicine.disease ,030104 developmental biology ,chemistry ,Metabolic Disorders ,biology.protein ,lcsh:Q ,Metabolic syndrome ,business ,Mathematics ,Lipoprotein - Abstract
Objective We tested the hypothesis that HDL-apolipoprotein A-I exchange (HAE), a measure of high-density lipoprotein (HDL) function and a key step in reverse cholesterol transport (RCT), is impaired in metabolic syndrome (MetSyn) patients who are asymptomatic for diabetes and cardiovascular disease. We also compared HAE with cell-based cholesterol efflux capacity (CEC) to address previous reports that CEC is enhanced in MetSyn populations. Methods HAE and ABCA1-specific CEC were measured as tests of HDL function in 60 MetSyn patients and 14 normolipidemic control subjects. Predictors of HAE and CEC were evaluated with multiple linear regression modeling using clinical markers of MetSyn and CVD risk. Results HAE was significantly reduced in MetSyn patients (49.0 ± 10.9% vs. 61.2 ± 6.1%, P < 0.0001), as was ABCA1-specific CEC (10.1 ± 1.6% vs. 12.3 ± 2.0%, P < 0.002). Multiple linear regression analysis identified apoA-I concentration as a significant positive predictor of HAE, and MetSyn patients had significantly lower HAE per mg/dL of apoA-I (P = 0.004). MetSyn status was a negative predictor of CEC, but triglyceride (TG) was a positive predictor of CEC, with MetSyn patients having higher CEC per mg/dL of TG, but lower overall CEC compared to controls. Conclusions MetSyn patients have impaired HAE that contributes to reduced capacity for ABCA1-mediated CEC. MetSyn status is inversely correlated with CEC but positively correlated with TG, which explains the contradictory results from earlier MetSyn studies focused on CEC. HAE and CEC are inhibited in MetSyn patients over a broad range of absolute apoA-I and HDL particle levels, supporting the observation that this patient population bears significant residual cardiovascular disease risk.
- Published
- 2017
- Full Text
- View/download PDF
48. Effects of niacin and omega-3 fatty acids on the apolipoproteins in overweight patients with elevated triglycerides and reduced HDL cholesterol
- Author
-
Gregory C. Shearer, Olga V. Savinova, Kristi Fillaus, and William S. Harris
- Subjects
Apolipoprotein E ,Adult ,Male ,medicine.medical_specialty ,Very low-density lipoprotein ,Glycosylation ,Time Factors ,Apolipoprotein B ,Niacin ,chemistry.chemical_compound ,Double-Blind Method ,Internal medicine ,Fatty Acids, Omega-3 ,medicine ,Humans ,Obesity ,Triglycerides ,Dyslipidemias ,Hypolipidemic Agents ,Metabolic Syndrome ,biology ,Triglyceride ,Cholesterol ,Cholesterol, HDL ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Endocrinology ,Apolipoproteins ,Treatment Outcome ,chemistry ,Delayed-Action Preparations ,South Dakota ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Drug Therapy, Combination ,Female ,Metabolic syndrome ,Cardiology and Cardiovascular Medicine ,Biomarkers ,Lipoprotein - Abstract
Prescription omega-3 acid ethyl esters (P-OM3) and extended release niacin (ERN) both have beneficial effects on plasma lipids and lipoproteins. The purpose of this study was to describe the effects of mono- and combination (Combo) therapy of these agents in patients with the metabolic syndrome.Very low density (VLDL), intermediate/low density (IDL/LDL, hereafter LDL), and high density lipoproteins (HDL) were isolated from 56 overweight patients with elevated triglyceride/HDL-C ratios at baseline and after 16 weeks of treatment with placebo, ERN (2g/day), P-OM3 (4g/day), or Combo and then analyzed by quantitative electrophoresis for apolipoproteins (apo) A1, A2, B, C2, C3 and E. Total plasma concentrations and the ratios of each apo with apoB (in VLDL and LDL) and with apoA1 (in HDL) were calculated. An apoC3 glycosylation index (a ratio between di- and mono-sialylated isoforms) was also determined in plasma and in each lipoprotein fraction.ERN reduced plasma apoB (-11%, p 0.05). Combo increased LDL apoE/apoB ratio (64%, p 0.01) and LDL apoA1/apoB (91%, p 0.05). ERN increased the apoC3 glycosylation index only in HDL (37%, p 0.05), whereas P-OM3 and Combo increased the index in whole plasma (48% and 49%, respectively, p 0.05 for both) and in every lipoprotein class (VLDL: 26%, p 0.01 and 26%, p 0.05; LDL: 55%, p 0.01 and 61%, p 0.01; HDL: 43%, p 0.001 and 44%, p 0.001, respectively). All findings were significant after adjustment for age, sex, body mass index (BMI), smoking, medications, and baseline apo value.ERN produced a beneficial reduction in plasma apoB. The enrichment of LDL with apoE and apoA1 was unique to the Combo group and might be beneficial owing to the atheroprotective properties of apoE and HDL2 (a likely source of apoA1 in LDL fraction). The effect of therapies on the apoC3 glycosylation index is a novel finding, the implications of which will require further study.
- Published
- 2014
49. Regulation of Gene Expression with Thyroid Hormone in Rats with Myocardial Infarction
- Author
-
Nathan Y. Weltman, Xijin Ge, A. Martin Gerdes, James V. Pottala, Olga V. Savinova, and Yue-Feng Chen
- Subjects
Anatomy and Physiology ,Microarrays ,Myocardial Infarction ,lcsh:Medicine ,Gene Expression ,Muscle Proteins ,030204 cardiovascular system & hematology ,Cardiovascular System ,Biochemistry ,Rats, Sprague-Dawley ,0302 clinical medicine ,Thyroid Hormone Treatment ,Nucleic Acids ,Gene expression ,Molecular Cell Biology ,Myocardial infarction ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Ventricular Remodeling ,Thyroid ,Genomics ,Animal Models ,medicine.anatomical_structure ,Female ,Biological regulation ,Research Article ,medicine.medical_specialty ,Thyroid Hormones ,Biological Data Management ,Biology ,03 medical and health sciences ,Model Organisms ,Internal medicine ,medicine ,Animals ,Ventricular remodeling ,030304 developmental biology ,Gene Expression Profiling ,lcsh:R ,Proteins ,Computational Biology ,medicine.disease ,Rats ,Gene expression profiling ,Endocrinology ,Gene Expression Regulation ,Rat ,lcsh:Q ,Hormone - Abstract
Introduction The expression of hundreds of genes is altered in response to left ventricular (LV) remodeling following large transmural myocardial infarction (MI). Thyroid hormone (TH) improves LV remodeling and cardiac performance after MI. However, the molecular basis is unknown. Methods MI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3 mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from LV non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform. Results Signals were detected in 13,188 genes (out of 22,523), of which the expression of 154 genes were decreased and the expression of 200 genes were increased in MI rats compared with Sham MI rats (false discovery rate (FDR)
- Published
- 2012
50. Myocyte changes in heart failure
- Author
-
Olga V. Savinova and A. Martin Gerdes
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Heart Ventricles ,Concentric hypertrophy ,Muscle hypertrophy ,Internal medicine ,medicine ,Eccentric ,Myocyte ,Animals ,Humans ,Myocytes, Cardiac ,Ventricular remodeling ,Heart Failure ,Ventricular Remodeling ,business.industry ,General Medicine ,medicine.disease ,Myocardial Contraction ,Heart failure ,Cardiology ,Disease Progression ,sense organs ,Animal studies ,Cardiology and Cardiovascular Medicine ,business - Abstract
Structural remodeling is a major feature of heart failure and typically precedes the development of symptomatic disease. Structural remodeling of the heart reflects changes in myocyte morphology. Disproportional myocyte growth is observed in pathologic concentric hypertrophy (myocyte thickening) and in eccentric dilated hypertrophy (myocyte lengthening). Alterations in myocyte shape lead to changes in chamber geometry and wall stress. Human and animal studies indicate that changes in myocyte morphology are reversible. Normalization or reversal of maladaptive cardiomyocyte remodeling should be a therapeutic aim that can prevent deterioration or improve cardiac function in heart failure.
- Published
- 2011
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.