Abstract
Recent studies have demonstrated that the renin angiotensin system (RAS) has profound effects on atherosclerosis, but the mechanisms underlying remain unclear. Macrophages play a central role in atherogenesis through scavenger receptor-mediated lipid accumulation, production of inflammatory cytokines and transformation of macrophages into foam cells. Macrophages express all components of RAS. Here we investigated the effects of Ang II on macrophage activation and foam cell formation, and underlying the mechanisms involved. In human THP1 macrophages, Ang II (100 nM) in time-dependent manner increased the mRNA expression of proinflammatory cytokines MCP1, TNFa, IL1b, IL6, CXCL9 and PAI1, Ang II also upregulated mRNA expression of CD36, TLR4 and hypoxia induced factor (HIF)1a. Knockdown of HIF1a by SiRNA prevented Ang II upregulation of CD36 and TLR4 expression, and significantly reduced the Ang II-induced proinflammatory cytokine expression. Next, we investigated the effects of Ang II on oxLDL uptake and foam cell formation, Ang II increased oxLDL uptake, which was prevented by either siRNA HIF1a or siRNA CD36. The incubation with oxLDL (50 ug/ml) for 72 hours result in lipid deposition in macrophage or foam cell formation, preincubation with Ang II further increased oxLDL-induced lipid deposition and foam cell formation, which was also prevented by either siRNA HIF1a or siRNA CD36. Infusion of Ang II into Apo E-/- mice significantly increased systolic blood pressure, the peripheral blood CD11b+/LyC6Hi inflammatory monocyte population and mRNA expression of IL1b and TNF1a in the peritoneal macrophages, Ang II also significantly increased atherosclerotic lesion formation. Hydrolazine normalized SBP but did not significantly reduce CD11b+/LyC6hi inflammatory monocyte population and atherosclerotic lesion formation in the apo E-/- mice treated with Ang II. The present study demonstrates, for the first time, that Ang II activates HIFa-CD36 pathway in human macrophage, which potentiate atherogenic lipid-induced macrophage activation and foam cell formation. Our novel findings may elucidate new mechanisms by which Ang II promotes atherogenesis through mediating macrophage activation and lipid metabolism.