Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase

Abstract

Oxidized low density lipoprotein (OxLDL) is one of the most important risk factors of cardiovascular disease. Here, we study the impact of OxLDL on endothelial progenitor cells (EPCs) and determine whether OxLDL affects EPCs by an inhibitory effect on endothelial nitric oxide synthase (eNOS). It was found that OxLDL decreased EPC survival and impaired its adhesive, migratory, and tubeformation capacities in a dose-dependent manner. However, all of the detrimental effects of OxLDL were attenuated by pretreatment of EPCs with lectin-like oxidized low density lipoprotein receptor (LOX-1) monoclonal antibody or L-arginine. Western blot analysis revealed that OxLDL dosedependently decreased Akt phosphorylation and eNOS protein expression and increased LOX-1 protein expression. Furthermore, OxLDL caused a decrease in eNOS mRNA expression and an increase in LOX-1 mRNA expression. These data indicate that OxLDL inhibits EPC survival and impairs its function, and this action is attributable to an inhibitory effect on

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

“…Oxidized LDL compounds lead to eNOS downregulation in mature endothelium to induce endothelial dysfunction. In a parallel manner it was demonstrated that oxLDL treatment also decreases both eNOS expression and function in EPC by induction of oxidative stress (61).…”

“…Tube formation of cultured late-outgrowth EPC is likewise partly dependent on eNOS function (33). OxLDL treatment reduces eNOS expression both in mature endothelium (102) and EPC, which resulted in decreased EPC survival and impaired adhesive properties (61). Likewise, LDL lipid apheresis increased peripheral EPC function in patients with refractory hyperlipidemia (66).…”

Endothelial Progenitor Cell Dysfunction in Diabetes Mellitus Type-2: Focus on Nitric Oxide System

“…Hyperlipidemia in apoE-deficient mice caused a low circulating EPC count, which correlated with enhanced atherosclerosis (Xu et al, 2003), while lipid aphaeresis treatment of patients with refractory hyperlipidemia stimulated EPC proliferation and increased eNOS activity (Patschan et al, 2009). Several in vitro studies on EPCs from DM-2 patients revealed that oxLDL reduced EPC survival, count, and function, as well as their eNOS activity and NO bioavailability (Imanishi et al, 2004;Ma et al, 2006). Elevated oxLDL levels exacerbate hyperglycemiaimpaired EPC migration; we recently showed that DM-2 patients with CAD have high plasma oxLDL levels, which were inversely correlated with EPC migration and NO production.…”

“…The deleterious effects of hyperglycemia on the vasculature are further exacerbated in DM-2 patients with elevated plasma lipid levels (Kanter et al, 2007). Several studies have shown that hyperglycemia or oxidized low-density lipoprotein (oxLDL) can reduce EPC count as well as impair EPC migration and proliferation by exerting harmful effects on the phosphatidylinositol-3 kinase (PI 3-K)/protein kinase B (PKB/Akt)/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling cascade (Callaghan et al, 2005;Chen et al, 2007;Krankel et al, 2005;Ma et al, 2006). This review presents and discusses the underlying metabolic alterations to the molecular mechanisms that are responsible for decreased EPC count and functionality in DM-2.…”

Lovastatin restores the function of endothelial progenitor cells damaged by oxLDL

“…Therefore, understanding the regulation of EPCs and their mechanisms may provide new insights into therapeutic neovascularization. Our group and others have investigated the detrimental effects of oxLDL, a risk factor for cardiovascular disease, on the number and activity of EPCs [3,4] . HMG-CoA reductase inhibitors (statins) have been developed as lipid-lowering drugs and have been documented to reduce the morbidity and mortality of coronary artery disease (CAD) [5] .…”