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 +/+→apoE -/-+sham; apoE -/-/AT1 +/+ →apoE -/-+UNx; apoE -/-/AT1 -/-→apoE -/-+sham; apoE -/-/AT1 -/-→apoE+UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the 2 UNx groups. ApoE -/-/AT1 +/+ →apoE -/-+UNx had significantly more atherosclerosis (16907±21473 versus 116071±8180 μm, 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 μm 2, P=NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE -/-/AT1 -/-→apoE -/-+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 -/-→apoE whereas it significantly increased both (by 2-and 6-fold, respectively) in apoE -/-/AT1 -/- →apoE -/- mice. Instead, apoE -/-/AT1 -/-→apoE -/- had 5-fold-increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M 2 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 M 1 and less M 2 through mechanisms that include increased apoptosis and impaired efferocytosis.
|Original language||English (US)|
|Number of pages||9|
|Journal||Arteriosclerosis, thrombosis, and vascular biology|
|State||Published - Dec 1 2011|
- angiotensin ii
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine