Microalbuminuria is associated with an increased risk for all-cause and cardiovascular mortality, but the pathophysiologic mechanism underlying the association between urinary albumin excretion and cardiovascular disease remains unclear. Here, we tested the hypothesis that enhanced endothelial apoptotic microparticles and decreased endothelial progenitor cell (EPC) levels might contribute to the pathophysiology of microalbuminuria or macroalbuminuria in cardiovascular disease. Flow cytometry was used to assess endothelial cell apoptosis and circulating EPC levels by quantification of circulating CD31+/annexin V+ apoptotic microparticles and EPC markers (defined as KDR+CD133+, CD34+CD133+, CD34+KDR+) in peripheral blood. In total, 125 patients with hypertension were enrolled in the study, of whom 80 patients (64%) were with normoalbuminuria (albumin excretion rate of 200 μg/min). Compared to hypertensive patients with normoalbuminuria, patients with microalbuminuria or macroalbuminuria had significantly more diabetes (P = 0.005), higher systolic blood pressure (P = 0.018), and elevated serum creatinine levels (P < 0.001). Among the three groups, patients with microalbuminuria or macroalbuminuria had significantly increased CD31+/annexin V+ apoptotic microparticles (1.8 ± 2.2 versus 3.0 ± 4.3 versus 5.2 ± 6.2%, P = 0.044) and decreased circulating EPC numbers (P < 0.05). By multivariate analysis, CD31+/annexin V+ apoptotic microparticle level was an independent predictor of urinary albumin excretion rate in hypertensive patients (P < 0.001). Microparticles isolated from hypertensive patients with microalbuminuria or macroalbuminuria attenuated EPC proliferation, migration, and increased H2O2 production, cellular senescence and apoptosis in comparison with those from hypertensive patients with normoalbuminuria. These findings suggest that hypertensive patients with microalbuminuria or macroalbuminuria have increased endothelial apoptotic microparticles and decreased circulating EPC levels, which may contribute to atherosclerotic disease progression and enhanced cardiovascular risk in hypertensive patients with nephropathy.

Objectives We sought to test the hypothesis that decreased plasma soluble receptor for advanced glycation end products (sRAGE) levels were associated with endothelial dysfunction in nondiabetic patients. Background sRAGE, a C-truncated secretary isoform of the receptor protein, has been shown to neutralize vascular damage mediated by advanced glycation end products, and has been implicated in atherogenesis. However, the relation between plasma sRAGE level and endothelial function remains unclear. Methods Plasma levels of sRAGE were examined in 180 nondiabetic participants with suspected coronary artery disease. Endothelial function was evaluated by endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. The primary end point was the combined occurrence of major adverse cardiovascular events, including nonfatal myocardial infarction, revascularization with percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. Results All participants were divided into three groups according to the magnitude of FMD: group 1 (FMD <3%), group 2 (FMD ≥3 and <6%), group 3 (FMD ≥6%). The plasma levels of sRAGE were significantly decreased in group 1 compared with groups 2 and 3 (676±270, 820±357, and 1140±451 pg/ml; P<0.001). By multivariate analysis, it was shown that the plasma sRAGE level was an independent predictor of endothelium-dependent FMD (R = 0.46; P809 pg/ml; P<0.05). By the Kaplan–Meier analysis, it was shown that enhanced plasma levels of sRAGE were associated with better major adverse cardiovascular event-free survival (P = 0.032). Conclusion The results indicate that plasma sRAGE levels are positively associated with endothelial function and predict cardiovascular events in nondiabetic participants with suspected coronary artery disease, suggesting its pivotal role in atherothrombosis.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved neovascularization in hindlimb ischemia mice; this effect may have been mediated by increased CXCR4 expression in EPCs.

Aim: There is uncertainty about the association between circulating concentrations of adiponectin and coronary heart disease risk, particularly in patients after acute myocardial infarction (AMI). The goal of this study was to determine whether plasma adiponectin levels could predict future cardiovascular events in patients after AMI, and to elucidate the role of adiponectin in cardioprotection. Methods: A total of 102 patients with AMI were enrolled. Plasma adiponectin levels were examined from blood samples collected 18 months after AMI. All subjects were followed-up for 43±12 months. The primary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization due to unstable angina, nonfatal MI, revascularization with percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. Results: A total of 30 MACE occurred, including one case of cardiovascular death, five cases of nonfatal MI, and nine cases of ischemic stroke. Patients with MACE had lower plasma adiponectin levels (p=0.013). In addition, adiponectin was positively associated with changes in left ventricular ejection fraction (p=0.005). All patients were divided into a high-adiponectin group (≥6.46 µg/mL) and a low-adiponectin group (<6.46 µg/mL). The incidence of MACE was significantly reduced in the high-adiponectin group (p=0.021). In multivariate Cox regression analysis that included adiponectin, classical risk factors, and medications, adiponectin was an independent predictor of MACE in patients after AMI (HR, 0.821; 95% CI, 0.691 to 0.974; p=0.024). Conclusions: The results indicate a potential association between plasma adiponectin levels and future cardiovascular events in patients after AMI. Moreover, plasma adiponectin concentrations appear to play a pivotal role in atherothrombosis and cardioprotection.

Arterial stiffness is a physiologic quantitative value used to measure arterial compliance. It is predictive of coronary atherosclerosis in patients with intermediate to high cardiovascular risk. However, a correlation between arterial stiffness and subclinical coronary atherosclerosis has yet to be established. Therefore, the purpose of this study was to evaluate arterial stiffness using an arterial stiffness index (ASI) and investigate its association with coronary artery plaque in patients with subclinical coronary atherosclerosis.