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Constricting pythons, known for their ability to consume infrequent, massive meals, exhibit rapid and reversible cardiac hypertrophy following feeding. Our primary goal was to investigate how python hearts achieve this adaptive response after feeding. Isolated myofibrils increased force after feeding without changes in sarcomere ultrastructure and without increasing energy cost. Ca2+ transients were prolonged after feeding with no changes in myofibril Ca2+ sensitivity. Feeding reduced titin-based tension, resulting in decreased cardiac tissue stiffness. Feeding also reduced the activity of sirtuins, a metabolically linked class of histone deacetylases, and increased chromatin accessibility. Transcription factor enrichment analysis on transposase-accessible chromatin with sequencing revealed the prominent role of transcription factors Yin Yang1 and NRF1 in postfeeding cardiac adaptation. Gene expression also changed with the enrichment of translation and metabolism. Finally, metabolomics analysis and adenosine triphosphate production demonstrated that cardiac adaptation after feeding not only increased energy demand but also energy production. These findings have broad implications for our understanding of cardiac adaptation across species and hold promise for the development of innovative approaches to address cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Abstract Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy.

Mechanical pressure overload and other stimuli often contribute to heart hypertrophy, a significant factor in the induction of heart failure. The UDP-glucose ceramide glycosyltransferase (UGCG) enzyme plays a crucial role in the metabolism of sphingolipids through the production of glucosylceramide. However, its role in heart hypertrophy remains unknown. In this study, UGCG was induced in response to pressure overload in vivo and phenylephrine stimulation in vitro. Additionally, UGCG downregulation ameliorated cardiomyocyte hypertrophy, improved cardiomyocyte mitochondrial oxidative stress, and reduced the ERK signaling pathway. Conversely, UGCG overexpression in cardiomyocytes promoted heart hypertrophy development, aggravated mitochondrial oxidative stress, and stimulated ERK signaling. Furthermore, the interaction between beta-1,4-galactosyltransferase 5 (B4GalT5), which catalyses the synthesis of lactosylceramide, and UGCG was identified, which also functions as a synergistic molecule of UGCG. Notably, limiting the expression of B4GalT5 impaired the capacity of UGCG to promote myocardial hypertrophy, suggesting that B4GalT5 acts as an intermediary for UGCG. Overall, this study highlights the potential of UGCG as a modulator of heart hypertrophy, rendering it a potential target for combating heart hypertrophy. [ABSTRACT FROM AUTHOR]

A variety of vegetable and fruit derived food oils are considered beneficial for human health due to their content of functional components including their positive effects in cardiovascular system. In addition to the favorable ratio of unsaturated versus saturated fatty acids, some of these oils include also other health beneficial compounds such as vitamins, minerals, pigments, enzymes and phenolic compounds. Particularly polyphenols have been documented to exert numerous positive effects in cardiovascular system including their anti-hypertensive, anti-atherogenic as well as cardio- and vasculo-protective effects in subjects suffering from various cardiovascular and cardiometabolic diseases, likely via their antioxidant, anti-inflammatory, anti-coagulant, anti-proliferative and anti-diabetic properties. However, it has not been proven so far whether the positive cardiovascular effects of polyphenol-rich food oils are, and to what measure, attributed to their phenolic content. Thus, the current review aims to summarize the main cardiovascular effects of major polyphenolrich food oils including olive, flaxseed, soybean, sesame and coconut oils, and to uncover the role of their phenolic compounds in these effects. [ABSTRACT FROM AUTHOR]

A variety of vegetable and fruit derived food oils are considered beneficial for human health due to their content of functional components including their positive effects in cardiovascular system. In addition to the favorable ratio of unsaturated versus saturated fatty acids, some of these oils include also other health beneficial compounds such as vitamins, minerals, pigments, enzymes and phenolic compounds. Particularly polyphenols have been documented to exert numerous positive effects in cardiovascular system including their anti-hypertensive, anti-atherogenic as well as cardio- and vasculo- protective effects in subjects suffering from various cardiovascular and cardiometabolic diseases, likely via their antioxidant, anti-inflammatory, anti-coagulant, anti-proliferative and anti-diabetic properties. However, it has not been proven so far whether the positive cardiovascular effects of polyphenol-rich food oils are, and to what measure, attributed to their phenolic content. Thus, the current review aims to summarize the main cardiovascular effects of major polyphenol-rich food oils including olive, flaxseed, soybean, sesame and coconut oils, and to uncover the role of their phenolic compounds in these effects.

After multivariable adjustment (energy intake, demographics, lifestyle factors, prevalent cardiovascular disease, diabetes, hypertension), HF risk was higher with a greater intake of eggs (1.23) and high-fat dairy (1.08) and HF risk was lower with greater whole-grain intake (0.93) [[32]]. Keywords: Western diet; cardiomyocyte; oxidative stress; bioactive agents; dietary fat; heart hypertrophy; cardiac failure EN Western diet cardiomyocyte oxidative stress bioactive agents dietary fat heart hypertrophy cardiac failure N.PAG N.PAG 18 08/29/22 20220801 NES 220801 In the ancient scripture Bhagavad Gita (3000 BCE) in India, Sattvic diets were advised for health, happiness, peace and longevity (https://www.holy-bhagavad-gita.org/chapter/17/verse/8, accessed on 15 June 2022). It seems that an increase in free fatty acids and oxidative dysfunction with reference to variability in biomarkers such as glucose levels, and levels of oxidative stress, predispose individuals to multifold greater inflammation and immune deficiency, leading to cardiac cell apoptosis and heart failure (HF) [[23], [25]]. Protective Dietary Patterns in the Prevention of Heart Failure In the USA, as well as in other Western countries, dietary patterns of patients with HF reveal a generally poor Western-type diet that may have a negative impact and a Mediterranean-style diet that may have a beneficial effect on pathophysiology and progression of CVDs and HF [[46], [52]]. Such diets may begin their adverse effects by causing twist dysfunction (Stage 1 HF) and later on sub-endocardial dysfunction (Stage 2 of HF) due to oxidative damage of proteins, enzymes, fatty acids and DNA. [Extracted from the article]

Background: Clinical evidence supports the influential role of genetic factors and intracellular signaling pathways in physiological cardiac hypertrophy. This study aimed to assess the response of the PI3K/mTORc1 signaling pathway in cardiac tissue to resistance training in obese rats with Type 2 Diabetes (T2D). Materials and Methods: A total of 21 male Wistar rats (Mean±SD weight: 220±20 g) were obese by 6 weeks High-Fat Diet (HFD) and randomly assigned to 1) non-diabetic, 2) control T2D, and 3) exercise diabetic groups. T2D was induced by intraperitoneal injection of streptozotocin (30 mg/kg) for diabetic groups. The exercise group did the resistance exercise program (5 times per week for 6 weeks). After exercise training, PI3K and mTORc1 expression in the left ventricle and the ratio of the left ventricle to heart and heart to body weight were compared between groups. The obtained data were compared by 1-way Analysis of Variance (ANOVA) (P

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Gizele Cabral Costa1 ,* Tadeu Lima Montagnoli2 ,* Jaqueline Soares Da Silva,2 Allan Kardec Nogueira de Alencar,2 Luis Eduardo Reina Gamba,2 Bryelle Eccard Oliveira Alves,1,2 Marina Moraes Carvalho da Silva,2 Margarete Manhães Trachez,2 José Hamilton M do Nascimento,2,3 Pedro Moreno Pimentel-Coelho,3 Rosália Mendez-Otero,3 Lidia Moreira Lima,2 Eliezer J Barreiro,2 Roberto Takashi Sudo,2 Gisele Zapata-Sudo1,2 1Programa de Pós-Graduação em Medicina (Cardiologia), Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; 2Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; 3Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil*These authors contributed equally to this workCorrespondence: Gisele Zapata-SudoInstituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-590, BrazilTel/ Fax +55-21-39386505Email gsudo@icb.ufrj.brIntroduction: Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC.Methods: Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups.Results: LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats.Conclusion: LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.Keywords: type 2 diabetes mellitus, diabetic cardiomyopathy, anti-TNF-α therapy, cardiac dysfunction, heart hypertrophy, Zucker diabetic fatty rat

The purpose of this study was a comparative assessment of pathological changes in the morpho-functional condition of the heart in groups of patients with arterial hypertension, divided by salt sensitivity.Material and methods. 93 patients with arterial hypertension (AH) and concomitant coronary heart disease were included in the study. All patients were subjected to a salt load, after which all patients were divided into groups of salt-sensitive (SS) and nonsalt-sensitive (NSS) patients. Along with this, the patient was replicated with an echocardiographic examination of the heart to determine the functional state of the heart muscle. Patients in the SS and NSS groups were compared by heart echocardiography results.Results. Left ventricular hypertrophy was found to be more prevalent in the group of SS patients compared to the NSS group (82.6% vs. 17.0%) and the differences between the groups were statistically significant (p

The ATP-sensitive K+ channel ([K.sub.ATP]) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.x or SUR mutations result in [K.sub.ATP] channelopathies, which reflect the physiological roles of these channels, including but not limited to insulin secretion, cardiac protection, and blood flow regulation. In this issue of the JCI, McClenaghan et al. explored one of the channelopathies, namely Cantu syndrome (CS), which is a result of one kind of [K.sub.ATP] channel mutation. Using a knockin mouse model, the authors demonstrated that gain-of-function [K.sub.ATP] mutations in vascular smooth muscle resulted in cardiac remodeling. Moreover, they were able to reverse the cardiovascular phenotypes by administering the [K.sub.ATP] channel blocker glibenclamide. These results exemplify how genetic mutations can have an impact on developmental trajectories, and provide a therapeutic approach to mitigate cardiac hypertrophy in cases of CS., Structural heterogeneity of the [K.sub.ATP] channels The ATP-sensitive K+ channel ([K.sub.ATP]) is composed of a large macromolecular complex in which four inwardly rectifying K+ channel (Kir6.1 or Kir6.2, referred to [...]

This study investigated whether ivabradine, a selective If current inhibitor reducing heart rate (HR), is able to improve survival and prevent left ventricular (LV) remodeling in isoproterenol‐induced heart damage. Wistar rats were treated for 6 weeks: controls (n = 10), ivabradine (10 mg/kg/day orally; n = 10), isoproterenol (5 mg/kg/day intraperitoneally; n = 40), and isoproterenol plus ivabradine (n = 40). Isoproterenol increased mortality, induced hypertrophy of both ventricles and LV fibrotic rebuilding, and reduced systolic blood pressure (SBP). Ivabradine significantly increased survival rate (by 120%) and prolonged average survival time (by 20%). Furthermore, ivabradine reduced LV weight and hydroxyproline content in soluble and insoluble collagen fraction, reduced HR and attenuated SBP decline. We conclude that ivabradine improved survival in isoproterenol‐damaged hearts. [ABSTRACT FROM AUTHOR]

The exact pathophysiology of heart failure (HF) is not yet known. Western diet, characterized by highly sweetened foods, as well as being rich in fat, fried foods, red meat and processed meat, eggs, and sweet beverages, may cause inflammation, leading to oxidative dysfunction in the cardiac ultra-structure. Oxidative function of the myocardium and how oxidative dysfunction causes physio-pathological remodeling, leading to HF, is not well known. Antioxidants, such as polyphenolics and flavonoids, omega-3 fatty acids, and other micronutrients that are rich in Indo-Mediterranean-type diets, could be protective in sustaining the oxidative functions of the heart. The cardiomyocytes use glucose and fatty acids for the physiological functions depending upon the metabolic requirements of the heart. Apart from toxicity due to glucose, lipotoxicity also adversely affects the cardiomyocytes, which worsen in the presence of deficiency of endogenous antioxidants and deficiency of exogenous antioxidant nutrients in the diet. The high-sugar-and-high-fat-induced production of ceramide, advanced glycation end products (AGE) and triamino-methyl-N-oxide (TMAO) can predispose individuals to oxidative dysfunction and Ca-overloading. The alteration in the biology may start with normal cardiac cell remodeling to biological remodeling due to inflammation. An increase in the fat content of a diet in combination with inducible nitric oxide synthase (NOSi) via N-arginine methyl ester has been found to preserve the ejection fraction in HF. It is proposed that a greater intake of high exogenous antioxidant restorative treatment (HEART) diet, polyphenolics and flavonoids, as well as cessation of red meat intake and egg, can cause improvement in the oxidative function of the heart, by inhibiting oxidative damage to lipids, proteins and DNA in the cell, resulting in beneficial effects in the early stage of the Six Stages of HF. There is an unmet need to conduct cohort studies and randomized, controlled studies to demonstrate the role of the HEART diet in the treatment of HF.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F- actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients., Introduction Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive, premature aging disease characterized by growth retardation, alopecia, loss of subcutaneous fat, aged-looking skin, bone abnormalities, and osteoporosis (1-3). A hallmark [...]

Background: The lack of clear standards for medical supervision of athletes considerably limits the ability to diagnose and prevent overstrain of the cardiovascular system. To date, in the Republic of Kazakhstan, an assessment of the significance of early cardiomarkers, reflecting the state of maladjustment of the heart to physical exertion among highly qualified athletes involved in martial arts, has not been performed. Aims: The aim of this study is to determine the level and diagnostic significance of cardiac biomarker IL1RL1 (sST2 - serum-soluble) and the role of psychological stress on the risk of cardiovascular disease in qualified sport veterans engaged in speed--strength sports. Methods: A prospective study on wrestlers was performed at the Centre for Sports Medicine and Rehabilitation (Almaty, Republic of Kazakhstan). All participants (n = 30) were males aged 30 to 44 years s, masters of sports of international class, and honoured masters of sports). The control group consisted of volunteers (VO) (n = 30). The sST2 level was determined before (BT) and immediately after (AT) training. Anthropometric and hemodynamic parameters of athletes were studied along with electrocardiography and echocardiography tests. Results: The average age of 30 athletes was 36.3 ± 0.5 years; the largest proportion of athletes was 35-39 years old (66.7%, n = 20); 6 sports veterans (20%) were 30-34 years old; the smallest proportion of athletes was under 40-44 years old (13.3%, n = 5). According to the electrocardiography (ECG) data, minor deviations from the norm (16.6 %) and abnormal ECG (30%) were identified. The echo-CG data showed "moderate" and "pronounced changes" in 40.0% and 60.0% of cases, respectively. The sST2 level of VO (337.1 ± 61.8 pg/mL) was lower than that of BT (570.1 ± 32.6 pg/mL) and AT (768.7 ± 71.6 pg/mL) (p < 0.05).IL1RL1 (ST2) showed high sensitivity in determining the maladaptation of the cardiovascular system to physical exertion in highly qualified sports veterans (p > 0.05). Conclusion: Athletes' sST2 levels exceeded thresholds both before and after training. Our findings indicate that the elevated sST2 concentrations in athletes can be used as the predictive value show maladaptation of the cardiovascular. However, it requires further intensive studies. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy (CH) is an important and independent predictor of morbidity and mortality. Through expression profiling, we recently identified a subset of genes (Dhrs7c, Decr, Dhrs11, Dhrs4, Hsd11b1, Hsd17b10, Hsd17b8, Blvrb, Pecr), all of which are members of the short‐chain dehydrogenase/reductase (SDR) superfamily and are highly expressed in the heart, that were significantly dysregulated in a rat model of CH caused by severe aortic valve regurgitation (AR). Here, we studied their expression in various models of CH, as well as factors influencing their regulation. Among the nine SDR genes studied, all but Hsd11b1 were down‐regulated in CH models (AR rats or mice infused with either isoproterenol or angiotensin II). This regulation showed a clear sex dimorphism, being more evident in males than in females irrespective of CH levels. In neonatal rat cardiomyocytes, we observed that treatment with the α1‐adrenergic receptor agonist phenylephrine mostly reproduced the observations made in CH animals models. Retinoic acid, on the other hand, stimulated the expression of most of the SDR genes studied, suggesting that their expression may be related to cardiomyocyte differentiation. Indeed, levels of expression were found to be higher in the hearts of adult animals than in neonatal cardiomyocytes. In conclusion, we identified a group of genes modulated in animal models of CH and mostly in males. This could be related to the activation of the fetal gene expression program in pathological CH situations, in which these highly expressed genes are down‐regulated in the adult heart.

Objective(s): To determine the effects of triiodothyronine (T3) intracoronary perfusion in isolated hearts and short-term administration in rats on the left ventricular (LV) phosphorylation patterns of Akt and ERK1/2. Materials and Methods: Cardiodynamic and hemodynamic parameters were evaluated in Langendorff- perfused hearts. Left ventricles were used for histomorphometric and Western blot analyses. Shortterm hyperthyroidism was established by T3 (500 µg.kg-1.d-1; subcutaneous injection) for 1 (T31d), 3 (T33d), and 10 (T310d) days. Results: Isolated hearts receiving T3 perfusion did not modify LV developed pressure, +dP/dtmax, -dP/dtmin, heart rate, and coronary perfusion pressure compared with vehicle-perfused hearts. P-ERK1/2 and p-Akt levels in LV tissues after 5, 15, or 60 min of T3 or vehicle perfusion were similar. Compared with their time-matched controls, isolated hearts of T33d and T310d rats exhibited LV hypertrophy and increased absolute values of +dP/dtmax and -dP/dtmin (i.e., positive inotropic and lusitropic effects). P-ERK1/2 decreased in LV tissues of T31d and T310d but not in those of T33d rats, and p-Akt levels augmented in left ventricles of T33d and stayed unaltered in those of T31d and T310d rats. Conclusion: T3 intracoronary perfusion did not alter cardiodynamics and hemodynamics nor influence the activation of Akt and ERK of normal hearts. Accordingly, the rapid non-genomic effects of T3 were not evident. Short-term T3 treatment provoked cardiac hypertrophy coincidental with increased LV function and associated with transient Akt activation and cyclic ERK1/2 inhibition; which implies activation of physiological hypertrophy signaling and deactivation of pathological hypertrophy signaling, respectively. [ABSTRACT FROM AUTHOR]

The consumption of high calorie-content diets is the first cause of obesity, probably the main health issue worldwide; however, the experimental evidences for evaluating the differential metabolic modifications of high-sucrose or high-fat diets are scare. We evaluated the metabolic outcomes of the obesity induced by the chronic consumption of high-sucrose (HS), high-fat (HF) or combined diets (HSHF), among the effect on the development of cardiac hypertrophy in Wistar rats. Rats from the HS, HF, and HSHS groups developed moderate obesity. Only the HS group showed increased triglycerides levels after four months. Increased leptin levels were observed in HS and HF groups without changes on cardiac hypertrophy; on the opposing, HSHF group presented hypertrophy without the changes in serum leptin. The three experimental groups showed a decreased expression of leptin receptors ObR-b. In our results, the kind of diet for the induction of obesity is relevant for the outcome of the pathological profile. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) is the first cause of death worldwide, generally exhibiting a high morbidity, high disability rate and high mortality especially in the elderly persons (>50 years old). Previously, extensive studies have demonstrated that cardiac fibrosis plays cardinal roles in the pathogenesis of CVDs. However, due to the unclear underlying mechanisms of cardiac fibrosis, its clinical intervention remains very lacking. Long non-coding RNAs (lncRNAs), a class of non-coding RNA but differing from microRNAs, are generally considered as transcripts with a length ranging 200 to 100 nucleotides. Recently, accumulating evidence showed that lncRNAs involve in the pathogenesis of cardiac fibrosis. Fendrr (FOXF1 adjacent non-coding developmental regulatory RNA), is a spliced long non-coding RNA transcribed bi-directionally with FOXF1 on the opposite strand. Fendrr has been demonstrated to be essential for normal development of the heart and body wall in mouse, and shows a good anti-fibrotic activity in pulmonary fibrosis. In this study, we aimed to explore the effects of Fendrr on cardiac fibrosis. Intriguingly, we first observed that lncRNA Fendrr was up-regulated in the heart tissues of transverse aortic constriction (TAC) induced cardiac fibrosis mouse models, determined by RT-QPCR. Loss-function of Fendrr significantly alleviated the cardiac fibrosis phenotypes induced by TAC, indicating that Fendrr is required for the pathogenesis of cardiac fibrosis. In mechanism, we demonstrated experimentally that Fendrr directly targeting miR-106b, by which the lncRNA promotes cardiac fibrosis (indicated by the elevation of Col1a1, Col3a1, CTGF and ACTA2 expression) in a miR-106b mediated manner. Collectively, our findings highlight the axis of Fendrr/miR-106b/Samd3 in the pathogenesis of cardiac fibrosis, which may be a promising target for clinical intervention target of cardiac fibrosis. • lncRNA Fendrr was up-regulated in the heart tissues of transverse aortic constriction. • Loss-function of Fendrr significantly alleviated the cardiac fibrosis phenotypes. • Fendrr directly targeting miR-106b, by which the lncRNA promotes cardiac fibrosis. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among others cardiac hypertrophy and atrial fibrillation. The aim of our study was to evaluate the impact of miR-221/222 on cardiac electrical remodeling. Cardiac miR expression was analyzed in a mouse model with altered electrocardiography parameters and severe heart hypertrophy. Next generation sequencing revealed 14 differentially expressed miRs in hypertrophic hearts, with miR-221 and -222 being the strongest regulated miR-cluster. This increase was restricted to cardiomyocytes and not observed in cardiac fibroblasts. Additionally, we evaluated the change of miR-221/222 in vivo in two models of pharmacologically induced heart hypertrophy (angiotensin II, isoprenaline), thereby demonstrating a stimulus-induced increase in miR-221/222 in vivo by angiotensin II but not by isoprenaline. Whole transcriptome analysis by RNA-seq and qRT-PCR validation revealed an enriched number of downregulated mRNAs coding for proteins located in the T-tubule, which are also predicted targets for miR-221/222. Among those, mRNAs were the L-type Ca2+ channel subunits as well as potassium channel subunits. We confirmed that both miRs target the 3′-untranslated regions of Cacna1c and Kcnj5. Furthermore, enhanced expression of these miRs reduced L-type Ca2+ channel and Kcnj5 channel abundance and function, which was analyzed by whole-cell patch clamp recordings or Western blot and flux measurements, respectively. miR-221 and -222 contribute to the regulation of L-type Ca2+ channels as well as Kcnj5 channels and, therefore, potentially contribute to disturbed cardiac excitation generation and propagation. Future studies will have to evaluate the pathophysiological and clinical relevance of aberrant miR-221/222 expression for electrical remodeling. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a major source of morbidity and mortality in the US. The multifunctional [Ca.sup.2+]/calmodulin-dependent kinase II (CaMKII) has emerged as a critical regulator of cardiac hypertrophy and failure, although the mechanisms remain unclear. Previous studies have established that the cytoskeletal protein [[beta].sub.IV]-spectrin coordinates local CaMKII signaling. Here, we sought to determine the role of a spectrin-CaMKII complex in maladaptive remodeling in HF. Chronic pressure overload (6 weeks of transaortic constriction [TAC]) induced a decrease in cardiac function in WT mice but not in animals expressing truncated [[beta].sub.IV]-spectrin lacking spectrin-CaMKII interaction ([qv.sub.3J] mice). Underlying the observed differences in function was an unexpected differential regulation of STAT3-related genes in [qv.sub.3J] TAC hearts. In vitro experiments demonstrated that [[beta].sub.IV]-spectrin serves as a target for CaMKII phosphorylation, which regulates its stability. Cardiac-specific [[beta].sub.IV]-spectrin-KO ([[beta].sub.IV]-cKO) mice showed STAT3 dysregulation, fibrosis, and decreased cardiac function at baseline, similar to what was observed with TAC in WT mice. STAT3 inhibition restored normal cardiac structure and function in [[beta].sub.IV]-cKO and WT TAC hearts. Our studies identify a spectrin-based complex essential for regulation of the cardiac response to chronic pressure overload. We anticipate that strategies targeting the new spectrin-based 'statosome' will be effective at suppressing maladaptive remodeling in response to chronic stress., IntroductionHeart failure (HF) represents a major burden on the US health care system, with 870,000 new cases annually and a total cost of $30.7 billion. By 2030, the incidence of [...]

The ubiquitin-proteasome system (UPS) degrades a protein molecule via 2 main steps: ubiquitination and proteasomal xdegradation. Extraproteasomal ubiquitin receptors are thought to couple the 2 steps, but this proposition has not been tested in vivo with vertebrates. More importantly, impaired UPS performance plays a major role in cardiac pathogenesis, including myocardial ischemia-reperfusion injury (IRI), but the molecular basis of UPS impairment remains poorly understood. Ubiquilin1 is a bona fide extraproteasomal ubiquitin receptor. Here, we report that mice with a cardiomyocyte-restricted knockout of Ubiquilin1 (Ubqln1-CKO mice) accumulated a surrogate UPS substrate (GFPdgn) and increased myocardial ubiquitinated proteins without altering proteasome activities, resulting in late-onset cardiomyopathy and a markedly shortened life span. When subject to regional myocardial ischemia-reperfusion, young Ubqln1-CKO mice showed substantially exacerbated cardiac malfunction and enlarged infarct size, and conversely, mice with transgenic Ubqln1 overexpression displayed attenuated IRI. Furthermore, Ubqln1 overexpression facilitated proteasomal degradation of oxidized proteins and the degradation of a UPS surrogate substrate in cultured cardiomyocytes without increasing autophagic flux. These findings demonstrate that Ubiquilin1 is essential to cardiac ubiquitination-proteasome coupling and that an inadequacy in the coupling represents a major pathogenic factor for myocardial IRI; therefore, strategies to strengthen coupling have the potential to reduce IRI., IntroductionTargeted removal of individual abnormal protein molecules in the cell is primarily performed by the ubiquitin-proteasome system (UPS). Hence, the UPS is vital to cellular protein quality control (PQC), which [...]

Bicuspid aortic valve is one of the most common congenital heart diseases with low manifestation in childhood and severe consequences in adults that determines the importance in early diagnostics of myocardial changes in this anomaly. According to the literature the polymorphisms in the genes of NFATC family could result both in impaired embriogenetic valves formation and development of postnatal myocardial hypertrophy. The aim of the study was to detect the early changes of intracardial hemodynamics at aortic valve in children with bicuspid aortic valve (BAV) and establish their interrelations to the signs of myocardial hypertrophy in these children. Materials and methods: Dopplerograhphic study of basic intracardiac hemodynamics parameters in 38 children with BAV and in 28 children of control group was conducted. The results were processed statistically by Student’s t-test, correlation analysis and multiple regression. Results: In the result of study the moderate concentric left ventricle myocardial hypertrophy development was detected in 62 % of children with BAV which is accompanying to significant increasing of blood flow velocity and pressure gradient at aortic valve. There were not established significant correlations between the parameters of hemodynamics at valve and left ventricle’s posterior wall depth and septum depth whereas the highest inputs of these values were obtained in the left ventricle systolic dimension and volume and less in the hypertrophic signs. Conclusions: In children with BAV the moderate concentric myocardial hypertrophy with significant changes of intracardial hemodynamics at aortic valve takes place with the highest inputs in left ventricle volumetric values The obtained data serves as a substantiation for the treatment and prevention of it further development. bicuspid aortic valve; children; heart hypertrophy; dopplerechocardiography; hemodynamics; regression analysis

We investigated to which extent polymorphisms of an individual affect the proteomic network. Consomic mouse strains (CS) were used to study the trans-effect of the cis-variant (polymorphic) proteins of the strain PWD/Ph on the proteins of the host strain C57BL/6J. The cardiac proteome of ten CSs was analyzed by 2-DE and MS. Cis-variant PWD proteins altered a high number of C57BL/6J proteins, but the number of trans-variant proteins differed considerably between different CSs. Cardiac hypertrophy was induced in CSs. We found that high variability of the proteome, as induced by polymorphisms in CS14, acts protective against the complex disease.

Cardiac hypertrophy (CH) is an important and independent predictor of morbidity and mortality. Through expression profiling, we recently identified a subset of genes (Dhrs7c, Decr, Dhrs11, Dhrs4, Hsd11b1, Hsd17b10, Hsd17b8, Blvrb, Pecr), all of which are members of the short‐chain dehydrogenase/reductase (SDR) superfamily and are highly expressed in the heart, that were significantly dysregulated in a rat model of CH caused by severe aortic valve regurgitation (AR). Here, we studied their expression in various models of CH, as well as factors influencing their regulation. Among the nine SDR genes studied, all but Hsd11b1 were down‐regulated in CH models (AR rats or mice infused with either isoproterenol or angiotensin II). This regulation showed a clear sex dimorphism, being more evident in males than in females irrespective of CH levels. In neonatal rat cardiomyocytes, we observed that treatment with the α1‐adrenergic receptor agonist phenylephrine mostly reproduced the observations made in CH animals models. Retinoic acid, on the other hand, stimulated the expression of most of the SDR genes studied, suggesting that their expression may be related to cardiomyocyte differentiation. Indeed, levels of expression were found to be higher in the hearts of adult animals than in neonatal cardiomyocytes. In conclusion, we identified a group of genes modulated in animal models of CH and mostly in males. This could be related to the activation of the fetal gene expression program in pathological CH situations, in which these highly expressed genes are down‐regulated in the adult heart. [ABSTRACT FROM AUTHOR]

Thrombospondin 4 (TSP-4) expression is induced in the heart and vasculature under pathological conditions, including myocardial infarction, myocardial pressure overload, and hypertension. TSP-4 is linked to remodelling processes, where it may affect extracellular matrix protein organization. In previous work, we studied the role of TSP-4 in small arteries during hypertension using Ang II-treated Thrombospondin 4 knockout ( Thbs4 −/− ) mice. We reported increased heart weight, as well as the occurrence of aortic aneurysms in the Ang II-treated Thbs4 −/− animals. In the present study, we further characterized the hearts and aortas from these animals. Hypertrophy of cardiomyocytes, together with perivascular fibrosis and inflammation was observed in the Ang II-treated Thbs4 −/− hearts. In the aortas, an increase in the aortic wall cross-sectional area (CSA) and wall thickness of the Ang II-treated Thbs4 −/− mice was found. More detailed investigation of the Ang II-treated Thbs4 −/− aortas also revealed the appearance of aortic dissections in the outer medial layer of the arteries, as well as pronounced inflammation. No differences were found in several other extracellular matrix-related parameters, such as number of elastin breaks or stress–strain relationships. However, at the ultrastructural level, collagen fibers showed alterations in diameter in the media and adventitia of the Ang II-treated Thbs4 −/− mice, in the area prone to dissection. In conclusion, we identified TSP-4 as an important protein in the development of cardiac hypertrophy and aortic dissections in Ang II-induced hypertension. [ABSTRACT FROM AUTHOR]

Abstract Fibroblast growth factor‐23 (FGF23) is a bone‐derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regulates the membrane abundance of the Na+:Cl− co‐transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/αKlotho complex, extracellular signal‐regulated kinase 1/2 (ERK1/2), serum/glucocorticoid‐regulated kinase 1 (SGK1), and with‐no lysine kinase‐4 (WNK4). Renal sodium (Na+) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and αKlotho deficiency. Conversely, gain of FGF23 function by injection of wild‐type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na+ uptake and membrane abundance of NCC, leading to volume expansion, hypertension, and heart hypertrophy in a αKlotho and dietary Na+‐dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23‐induced volume expansion and heart hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na+ reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients.