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OBJECTIVE: Peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists (thiazolidinediones [TZDs]) are used for the treatment of diabetes. Bone marrow-derived endothelial progenitor cells (EPCs) improve vascular function and predict cardiovascular risk. The effect of pioglitazone therapy on EPCs was examined. RESEARCH DESIGN AND METHODS AND RESULTS: We performed a prospective, randomized, double-blind study on patients with documented stable coronary artery disease and normal glucose tolerance. Of 54 patients with normal fasting glucose levels, 18 showed impaired glucose tolerance and 36 patients with normal glucose tolerance were randomized to 30-day treatment with pioglitazone (45 mg) or placebo in addition to optimal medical therapy. All patients in the TZD group showed an increase of adiponectin levels as an indicator of compliance (11.4 +/- 1.1 to 36.8 +/- 2.1 microg/ml; P < 0.001). TZD, but not placebo, decreased mean high-sensitivity C-reactive protein to 43 +/- 19% (P < 0.05). Pioglitazone increased CD34(+)/kinase insert domain receptor(+) EPCs to 142 +/- 9% and cultured 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled acetylated LDL(+)/lectin(+) EPCs to 180 +/- 3% (P < 0.05). EPC numbers were not changed in the placebo group. TZD increased the SDF-1-induced migratory capacity to 146 +/- 9% per EPC number (P < 0.05) and upregulated the clonogenic potential of EPCs, increasing the colony-forming units to 172 +/- 12% (P < 0.001). In cultured human EPCs, TZD increased EPC numbers and migration and reduced NADPH-oxidase activity. The TZD effect was reversed by the PPAR gamma antagonist GW9662 and mimicked by treatment with adiponectin. CONCLUSIONS: The PPAR gamma agonist pioglitazone increases the number and function of EPCs in patients with coronary artery disease. The effect represents a potential regenerative mechanism in atherosclerosis and is observed in normoglycemic individuals with stable coronary artery disease. [ABSTRACT FROM AUTHOR]

Aims: Angiogenesis is defined as the sprouting of capillaries from pre-existing vasculature. It is a complex process that includes endothelial proliferation, migration, and tube formation. Previous data have demonstrated a high expression level of manganese-superoxide dismutase (MnSOD) in endothelial cells and suggested an important role of MnSOD in several cardiovascular diseases. In addition, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) has been shown to mimic some of the effects of MnSOD in various tissues. However, its effect on the vasculature remains unknown., Methods and Results: HUVECs were treated with MnTBAP. Migration, tube formation, and capillary sprouting assays were performed to evaluate the pro-angiogenic effect in vitro. Matrigel plug assay was performed to assess capillary ingrowth in vivo. Compared to control, treatment with MnTBAP revealed increased cell migration, tube formation and capillary sprouting along with more capillary ingrowth in the Matrigel plug assay. This effect was mediated through a mitofusin (Mfn)-1-dependent pathway. Expression of Tie-2, Ang-2 and VEGF mRNA was increased in muscle tissues after ligation in MnTBAP treated mice. However, revascularization in the hindlimb ischemia model was not statistically significant at day 10 in MnTBAP treated mice., Conclusion: In summary, our data demonstrate a strong pro-angiogenic, but less pro-arteriogenic effect of MnTBAP in HUVECs mediated by Mfn-1., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The mechanisms of the harmful cardiovascular effects of small particulate matter are incompletely understood. Endothelial progenitor cells (EPCs) predict outcome of patients with vascular disease. The aim of our study was to examine the effects of diesel exhaust particles (DEP) on EPC and on the associated vascular damage in mice. C57Bl/6 mice were exposed to DEP. 2 μg DEP/day was applicated intranasally for 3 weeks. Exposure to DEP reduced DiLDL/lectin positive EPC to 58.4 ± 5.6% (p < 0.005). Migratory capacity was reduced to 65.8 ± 3.9% (p < 0.0001). In ApoE(-/-) mice, DEP application reduced the number of EPC to 75.6 ± 6.4% (p < 0.005) and EPC migration to 58.5 ± 6.8% (p < 0.005). Neoangiogenesis was reduced to 39.5 ± 14.6% (p < 0.005). Atherogenesis was profoundly increased by DEP treatment (157.7 ± 18.1% vs. controls, p < 0.05). In cultured human EPC, DEP (0.1-100 μg/mL) reduced migratory capacity to 25 ± 2.6% (p < 0.001). The number of colony-forming units was reduced to 8.8 ± 0.9% (p < 0.001) and production of reactive oxygen species was elevated by DEP treatment (p < 0.001). Furthermore, DEP treatment increased apoptosis of EPC (to 266 ± 62% of control, p < 0.05). In a blood-brain barrier model, DEP treatment impaired endothelial cell integrity during oxygen-glucose deprivation (p < 0.001). Diesel exhaust particles impair endothelial progenitor cell number and function in vivo and in vitro. The reduction in EPC was associated with impaired neoangiogenesis and a marked increase in atherosclerotic lesion formation.

Aims: Microalbuminuria (MAU) is a marker for endothelial dysfunction and a predictor of increased cardiovascular risk. Physical activity improves endothelial function. This analysis aims to explore the impact of regular physical exercise on the prevalence and the degree of MAU in hypertensive individuals at high cardiovascular risk., Methods and Results: The International Survey Evaluating microAlbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH) studied the prevalence of MAU in 20,786 hypertensive patients at high cardiovascular risk. Herein, we investigated the relationship between self-reported physical activity and MAU in relation to the number of cardiovascular risk factors, medication and co-morbidities. A total of 7123 patients (34.3%) performed regular physical exercise (moderate or strenuous, at least 4 hours per week). The prevalence of MAU was significantly lower in active than in inactive patients (54% vs 61%; P < 0.0001). This association was observed in all classes of blood pressure and heart rate and was similar in patients with and without diabetes mellitus. Urinary albumin excretion (UAE) was lower in active than in inactive patients (UAE 80 mg/l: 11.6% vs 13.5%, P < 0.0001; UAE 150 mg/l: 7.5% vs 10%; P < 0.0001). In a multivariate analysis adjusted for age, gender, blood pressure, heart rate, renal function, medication and comorbidities, regular physical activity was associated with a 25% lower risk for MAU (odds ratio (OR) 0.75; 95% confidence interval (CI), 0.67-0.84; P < 0.0001). Risk reduction for MAU was more pronounced in strenuously active (OR 0.66; 95%CI, 0.47-0.95; P < 0.05) than in moderately active patients (OR 0.76; 95%CI, 0.68-0.85; P < 0.0001)., Conclusion: In hypertensive patients at high cardiovascular risk, physical activity is an independent predictor for a decreased risk of microalbuminuria.

Objective: Telomeres and associated proteins are regulators of cellular survival, regeneration and aging. PPAR-γ agonists may mediate vascular effects in addition to insulin sensitizing. We therefore examined whether pioglitazone regulates vascular telomere biology., Methods and Results: C57/Bl6 mice were randomized to treatment with pioglitazone (20mg/kg i.p. daily) or vehicle for 4 weeks (n = 6-8 per group). Telomere repeat amplification protocols showed a 2-fold increase of aortic telomerase activity in the pioglitazone group. Telomere repeat-binding factor 2 protein and mRNA levels (236%+172% of vehicle) as well as phosphorylation of protein kinase Akt (479% of vehicle) were up-regulated. Western blots demonstrated reduced aortic expression of senescence markers p16, cell-cycle checkpoint kinase 2 and p53. These regulatory mechanisms were independent of acute changes of telomere length. Similar observations were made in mononuclear cells (MNC) from these mice and in cultivated bovine aortic endothelial cells, human MNC and endothelial progenitor cells (EPC). Telomerase activation by pioglitazone in cultivated cells was prevented by Akt inhibitors. To test the functional relevance of the findings, isolated mononuclear cells (MNC) were exposed to H(2)O(2). MNC from pioglitazone-treated mice exhibited reduced apoptosis (AnnexinV-FACS). In vivo, lipopolysaccharide-induced aortic endothelial apoptosis was potently prevented in pioglitazone-treated animals (hairpin oligonucleotide assay). Both, up-regulation of telomere-regulating proteins and prevention of oxidative stress-induced aortic apoptosis, were absent in telomerase reverse transcriptase (TERT)-deficient mice., Conclusions/interpretation: Pioglitazone treatment up-regulates telomerase activity, telomere-stabilizing proteins and reduces senescence markers in vascular cells. These effects and the reduction of LPS-induced endothelial apoptosis by thiazolidinediones depend on TERT. The findings underscore the important role of telomere-regulating proteins for vascular cell function and survival., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

ROCKs are important regulators of the actin cytoskeleton. Because changes in the actin cytoskeleton underlie vascular contractility and remodeling, inflammatory cell recruitment, and cell proliferation, it is likely that the Rho/ROCK pathway will play a central role in mediating vascular function. Indeed, increased ROCK activity is observed in cerebral and coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis, and atherosclerosis. Recent experimental and clinical studies suggest that inhibition of ROCK could be a promising target for the treatment of cardiovascular disease. For example, inhibition of ROCK might be the underlying mechanism by which statins or HMG-CoA reductase inhibitors exert their therapeutic benefits beyond cholesterol reduction. In this review we summarize current understanding of the crucial role of RhoA/ROCK pathway in the regulation of vascular function and discuss its therapeutic potential in the treatment of atherosclerosis and vascular disease., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Sca-1 and VEGFR-2 positive pro-angiogenic cells (PAC) predict outcome of patients with vascular disease. Activation of the renin-angiotensin-aldosterone system impairs PAC function. The effects of the direct renin inhibitor aliskiren on PAC numbers and function are not known. Treatment of C57Bl/6 mice and Apo E(-/-) mice on high-cholesterol diet with aliskiren, 25 mg/kg/day s.c. for 3-6 weeks, reduced systolic and diastolic blood pressure by -11.5 and -13.7% compared to vehicle. Aliskiren increased Sca-1/VEGFR-2 positive PAC in the blood (159 ± 14%) and spleen-derived DiLDL/lectin positive PAC (180 ± 21%). Migratory capacity of PAC was increased to 165 ± 16%. In cultured human PAC, aliskiren dose-dependently increased the number of colony forming units to 152 ± 9% (1 μmol/l) and 187 ± 7% (10 μmol/l), which was prevented by the eNOS inhibitor LNMA. H₂O₂-induced apoptosis of cultured human PAC was reduced to 77 ± 23%. In Apo E(-/-) mice, aliskiren reduced atherosclerotic plaque area in the aortic sinus by 58 ± 4%. Circulating Sca-1/VEGFR-2 positive PAC were upregulated to 180 ± 25% and migratory capacity of PAC was increased to 127 ± 7%. Aliskiren reduced vascular NADPH oxidase activity to 41.6 ± 6.7%. Despite similar blood pressure lowering, treatment with hydralazine (25 mg/kg/day) did not significantly influence atherogenesis or PAC. Treatment of C57Bl/6 mice with a lower dose of aliskiren (15 mg/kg/day) did not affect blood pressure but increased cultured DiLDL/lectin positive PAC to 229 ± 30% and their migratory capacity to 214 ± 24%. Aliskiren increased number and function of PAC in mice and prevented atherosclerotic lesion formation. The effects were observed independent of blood pressure lowering.

PPAR-gamma agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235+/-60%) and the bone marrow (166+/-30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231+/-21% (n=24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246+/-73% and increased expression of telomere repeat-binding factor 2 by 320+/-50%. In vivo neoangiogenesis was increased two-fold (214+/-42%, 20 days). The NOS inhibitor L-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65+/-2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H(2)O(2)-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases.

Bone marrow derived endothelial progenitor cells (EPC) improve endothelial function and neoangiogenesis. Prostaglandin E1 (PGE1) is used for the treatment of patients with peripheral artery disease (PAD). However, the molecular effects are only partially understood. Treatment of C57/Bl6 mice with PGE1, 10 microg/kg BW increased the number of circulating Sca-1/VEGFR-2 positive EPC in the blood compared to vehicle (122+/-7% and 119+/-6% after 10 and 20 days). EPC in the bone marrow were upregulated to 125+/-11% (10 days) and 142+/-15% (20 days). PGE1 increased DiLDL/Lectin positive spleen-derived EPC to 170+/-20% and 174+/-14% after 10 and 20 days. Treatment with PGE1 enhanced in-vivo neoangiogenesis by 2-fold (disk assay, 218+/-27%). PGE1 enhanced the SDF-1 induced migratory capacity per number of EPC to 140+/-11%, 146+/-22% and 160+/-16% after 10, 14 and 20 days. Greater migratory capacity was associated with upregulation of expression of telomere repeat-binding factor (TRF2). EPC of PGE1-treated mice were characterized by reduced apoptosis. Similarly, PGE1 prevented H(2)O(2)-induced apoptosis in cultured human EPC. The effect is mediated by PI3-kinase. The effects of PGE1 on EPC were completely prevented by co-treatment with the NO-inhibitor L-NAME, 50 mg kg(-1) p.o. Treatment with the prostaglandin I2 derivative iloprost (10 microg/kg BW, 20 days) did not alter EPC numbers or function. Physical exercise is the basis of the treatment of patients with PAD. Voluntary running increased EPC numbers in mice. Treatment with PGE1 resulted in an additional increase of Sca-1/VEGFR-2- and DiLDL/lectin positive EPC as well as migration. n=10-24 for all groups, all effects p<0.05. In summary, prostaglandin E1 increases the number of EPC in the blood and the bone marrow in mice. The effect is additive to physical exercise, depends on nitric oxide and is characterized by reduction of PI3-kinase mediated apoptosis. PGE1-mediated upregulation of EPC is associated with improved EPC function and enhanced angiogenesis.

Background: Assessment of depression in schizophrenia is of great importance as depressive signs and symptoms and suicidality are highly prevalent in patients with schizophrenic disorders. The Calgary Depression Rating Scale (CDSS) is the standard assessment instrument for that purpose due to its proven reliability and validity. However, so far no reference values derived from an adequate healthy sample have been published., Methods: The present study analyzed CDSS item scores and summary scores in 154 healthy subjects (49% female, mean age 32.8+/-11.7 years) selected from studies as controls for schizophrenic patients., Results: The total CDSS score was 2.6+/-2.7 (range 0-12), about 1/3 of healthy subjects had scores=0. Gender differences were observed with respect to "early awakening" and "suicidal ideation" with higher scores in females. Total CDSS scores (r=-0.17, P=0.03) and single items were slightly negatively correlated with age. The psychometric properties of the CDSS scale were satisfying (corrected item-score correlations r(tc)=0.33-0.61, internal consistency Cronbach's alpha=0.76, one-dimensional factor structure). CDSS total scores showed a skewed distribution fitting the upper part of a normal distribution. Based on the empirical distribution of CDSS values, reference values were listed for the total group of healthy subjects, and for females and males separately., Conclusions: The results corroborate the favourable psychometric properties of the CDSS found previously in clinical samples in a healthy control group. The reference values reported here can assist the clinical use and interpretation of CDSS values and emphasize the usefulness of the CDSS for a thorough assessment of depression and suicidality in schizophrenia.