Macrophage Polarization by Angiotensin II-Type 1 Receptor Aggravates Renal Injury-Acceleration of Atherosclerosis

作者：Yamamoto Suguru; Yancey Patricia G; Zuo Yiqin; Ma Li Jun; Kaseda Ryohei; Fogo Agnes B; Ichikawa Iekuni; Linton MacRae F; Fazio Sergio; Kon Valentina^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(12): 2856-U277.

DOI：10.1161/ATVBAHA.111.237198

• angiotensin ii
• atherosclerosis
• kidney
• macrophages

Objective-Angiotensin II is a major determinant of atherosclerosis. Although macrophages are the most abundant cells in atherosclerotic plaques and express angiotensin II type 1 receptor (AT1), the pathophysiologic role of macrophage AT1 in atherogenesis remains uncertain. We examined the contribution of macrophage AT1 to accelerated atherosclerosis in an angiotensin II-responsive setting induced by uninephrectomy (UNx).
Methods and Results-AT1(-/-) or AT1(+/+) marrow from apolipoprotein E deficient (apoE(-/-)) mice was transplanted into recipient apoE-/- mice with subsequent UNx or sham operation: apoE(-/-)/AT1(+/+) -> 3apoE(-/-) +sham; apoE(-/-)/AT1(+/+) 3apoE(-/-) +UNx; apoE(-/-)/AT1(-/-) -> 3apoE(-/-) +sham; apoE(-/-)/AT1(-/-) -> 3apoE(-/-) +UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the 2 UNx groups. ApoE(-/-)/AT1(+/+) 3apoE(-/-) +UNx had significantly more atherosclerosis (16907 +/- 21473 versus 116071 +/- 8180 mu m(2), P < 0.05). By contrast, loss of macrophage AT1 which reduced local AT1 expression, prevented any effect of UNx on atherosclerosis (77174 +/- 9947 versus 75714 +/- 11333 mu m(2), P = NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE(-/-)/AT1(-/-) 3apoE(-/-) +UNx had fewer classically activated macrophage phenotype (M1) and more alternatively activated phenotype (M2). Further, UNx did not affect plaque necrosis or apoptosis in apoE(-/-)/AT1(-/-) 3apoE(-/-) whereas it significantly increased both (by 2- and 6-fold, respectively) in apoE(-/-)/AT1(+/+) 3apoE(-/-) mice. Instead, apoE(-/-)/AT1(-/-) 3apoE(-/-) had 5-fold-increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M2 macrophages, and a more efficient phagocytic function of AT1(-/-) macrophages versus AT1(+/+).
Conclusion-AT1 receptor of bone marrow-derived macrophages worsens the extent and complexity of renal injury-induced atherosclerosis by shifting the macrophage phenotype to more M1 and less M2 through mechanisms that include increased apoptosis and impaired efferocytosis. (Arterioscler Thromb Vasc Biol. 2011;31:2856-2864.)

• 出版日期2011-12