Macrophage Polarization by Angiotensin II-Type 1 Receptor Aggravates Renal Injury-Acceleration of Atherosclerosis
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 μm2, 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 μm2, 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 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.
- Received May 26, 2011.
- Accepted September 26, 2011.
- © 2011 American Heart Association, Inc.