肾素（前体）受体影响ABCA1/G1介导的胆固醇外流及参与大鼠动脉粥样硬化的机制研究

Renin-Angiotensin-Aldosterone system (RAAS) plays a significant role in lipid metabolism and atherosclerosis through angiotensin II (AngII). AngII downregulated ATP-binding cassette A1 (ABCA1) expression and decreased cholesterol efflux in macrophages and caused atherosclerosis. Recent studies have demonstrated that (pro)renin receptor [(P)RR], a new member of RAAS, play a pathological role in heart failure and renal fibrosis independent of AngII. Yet the effect of (P)RR on macrophage ABCA1/G1 expression and cholesterol efflux is not known. Our preliminary studies showed that (P)RR mRNA and protein were decreased in macrophages from hypertensive patients with high renin activity. In these patients ABCA1 mediated cholesterol efflux was also impaired. These data indicated that (P)RR activation may inhibit ABCA1/G1 function and decrease the cholesterol efflux. In this proposed study, we plan to construct transgenic rats with (P)RR overexpressed in macrophages. And evaluate ABCA1/G1 mediated cholesterol efflux in macrophages and foam cell formation in those rats. In vitro, we will also explore the molecular mechanism of ABCA1 expressions regulated by (P)RR using cultured macrophages with (P)RR overexpressed . Eventually, to clarify the mechanistic role of (P)RR on ABCA1/G1 expression and function, cholesterol efflux and atherosclerosis. The results may provide a new pharmacological target for atherosclerosis therapy.

传统RAAS通过血管紧张素Ⅱ(AngⅡ)抑制ATP结合盒转运子A1/G1(ABCA1/G1)介导巨噬细胞胆固醇外流参与动脉粥样硬化(AS)，新成员肾素前体受体(P)RR有不依赖AngⅡ的致心衰、肾纤维化等病理作用。但其是否可以直接调控ABCA1/G1及巨噬细胞胆固醇外流尚待研究。我们前期研究发现高肾素高血压患者单核细胞(P)RR表达增强，ABCA1表达及介导胆固醇外流率降低。提示(P)RR激活可能通过调控巨噬细胞ABCA1/G1的表达及功能影响胆固醇外流，参与AS。本研究通过构建巨噬细胞过表达(P)RR的大鼠模型，从整体动物水平观察(P)RR抑制ABCA1/G1表达导致胆固醇外流功能下降，巨噬细胞泡沫化形成动脉粥样硬化斑块；揭示(P)RR调控ABCA1启动子抑制性结合域的分子机制。以阐明(P)RR通过直接抑制ABCA1/G1功能加速AS的机制，为阻断(P)RR治疗AS提供RAAS的新靶点。

我们研究发现，用prorenin干预小鼠后(P)RR过度激活，小鼠血浆中HDL-c水平显著降低，LDL-c水平显著增高，同时主动脉根部动脉粥样硬化斑块面积显著增大。其中肝脏中ABCA1的表达及介导的胆固醇外流率降低。机制研究发现，prorenin激活(P)RR，ABCA1的mRNA稳定性降低，通过抑制核受体PPARγ/LXR，抑制ABCA1转录翻译及介导的胆固醇外流功能。这一机制可能参与血浆中HDL-C的水平下降。同时发现prorenin激活巨噬细胞 (P)RR，导致ABCA1及ABCG1表达及介导胆固醇外流的功能显著降低，从而促进巨噬细胞泡沫化，形成动脉粥样硬化斑块，加速AS发展。以上研究结果提示(P)RR促进AS发展独立于血管紧张素II之外，为(P)RR抑制剂可能逆转(P)RR的病理作用提供了理论依据。