Circulating angiogenic stem cells in diabetes.

Circulating angiogenic stem cells (CACs) are rare cells found in peripheral blood that have been shown to contribute to endothelial repair and new blood vessel formation. These cells could be biomarkers and/or therapeutic targets for the assessment and prevention of cardiovascular disease (CVD), which is the leading cause of mortality globally and in the United States. Diabetes is an independent risk factor for CVD, and there are inconsistent reports on the role of CACs in diabetic vasculopathy. To study this further we tested the hypothesis that diabetes depletes circulating levels of CACs, due to hyperglycemia or insulin resistance and that CAC depletion contributes to vascular dysfunction associated with diabetes. It was further proposed that in subjects with diabetes CACs may be dysfunctional. Studies presented here identify one subgroup of CAC, (CAC-3: AC133+/CD34+/CD45dim/CD31+/CD14-), that is reduced in diabetes and whose levels are negatively associated with hyperglycemia and endothelial function. Furthermore we found that increased plasma levels of soluble ICAM-1 are also associated with decreased CAC-3 levels and VEGFR2 surface expression. Our results also show that subjects with diabetes have CACs with decreased adhesive and proliferative capacity. These studies identify the specific CAC phenotypes that are affected by diabetes and suggest that CAC levels are a robust index of long-term glycemic control and that their levels reflect hyperglycemia rather than insulin levels. These studies also suggest that CAC levels may be monitored by bedside assessment of endothelial function

Association Between Residential Greenness and Cardiovascular Disease Risk

Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on β-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity

Metabolic remodeling of white adipose tissue in obesity

Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇o2, V̇co2, and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity

Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction

Circulating angiogenic cells (CACs) of various described phenotypes participate in the regeneration of the damaged endothelium, but the abundance of these cells is highly influenced by external cues including diabetes. It is not entirely clear which CAC populations are most reflective of endothelial function nor which are impacted by diabetes. To answer these questions, we enrolled a human cohort with variable CVD risk and determined relationships between stratified levels of CACs and indices of diabetes and vascular function. We also determined associations between CAC functional markers and diabetes and identified proangiogenic molecules which are impacted by diabetes. We found that subjects with low levels of CD34+ /AC133+ /CD31+ /CD45dim cells (CAC-3) had a significantly higher incidence of diabetes (p = 0.004), higher HbA1c levels (p = 0.049) and higher CVD risk scores. Furthermore, there was an association between low CAC-3 levels and impaired vascular function (p = 0.023). These cells from diabetics had reduced levels of CXCR4 and VEGFR2, while diabetics had higher levels of certain cytokines and pro-angiogenic molecules. These results suggest that quantitative and functional defects of CD34+ /AC133+ /CD31+ /CD45dim cells are associated with diabetes and vascular impairment and that this cell type may be a prognostic indicator of CVD and vascular dysfunction

Depletion of Circulating CD34+/KDR+ Cells in Type 2 Diabetes is Associated With Glycemic Control

Background and Hypothesis: Circulating levels of endothelial progenitor cells have been found to be predictive of cardiovascular events and mortality. Although the levels of these cells reflect overall cardiovascular disease (CVD) risk, studies assessing their association with major CVD factors - hypertension, dyslipidemia and diabetes have yielded inconsistent results and the mechanisms contributing to EPC depletion remain unknown. We hypothesized that EPC depletion occurring in diabetes is mediated in part by hyperglycemia or insulin resistance. Methods: Circulating levels of progenitor cells were measured by flow cytometry in 108 diabetic or non-diabetic subjects recruited from the University of Louisville Health System. Reactive hyperemia index (RHI) was measured by the EndoPAT. Demographic information was acquired and blood, plasma and urine were used for biochemical analyses. Subjects were divided into high and low EPC count groups using the median split. Data was analyzed using a Chi-square test, a two-sample rank sum test, and univariable and multivariable logistic regressions. Results: Levels of CD34+/KDR+/CD14−/CD16− cells (EPCs) were associated with the diagnosis of diabetes (p=0.04), but not with other demographic covariates, hypertension or dyslipidemia. Levels of CD34+, AC133+ and CD34+/AC133+/CD45+ cells also displayed significant association with diabetes (p=0.038, 0.014 and 0.038 respectively). RHI was strongly associated with diabetes (p\u3c0.0001) hypertension and dyslipidemia, however, no significant associations were observed between RHI and EPCs. EPC levels were inversely associated with HbA1C (p=0.047) and fasting blood glucose, but not with insulin levels or the HOMA-IR score. In the complete model, the association between EPCs and diabetes was strengthened by the inclusion of RHI, indicating more robust EPC depletion in those with endothelial dysfunction. Conclusion: Circulating EPC levels are a robust index of long-term glycemic control and are associated with hyperglycemia rather than contemporaneous insulin levels or endothelial dysfunction. These findings may help in prognosis and early identification of CVD risk in patients with diabetes, independent of other risk estimates