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. 2011 Dec;31(12):2856-64.
doi: 10.1161/ATVBAHA.111.237198. Epub 2011 Oct 6.

Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis

Suguru Yamamoto  1 , Patricia G Yancey, Yiqin Zuo, Li-Jun Ma, Ryohei Kaseda, Agnes B Fogo, Iekuni Ichikawa, MacRae F Linton, Sergio Fazio, Valentina Kon
Affiliations

Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis

Suguru Yamamoto et al. Arterioscler Thromb Vasc Biol. 2011 Dec.

Abstract

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(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 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 M2 macrophages, and a more efficient phagocytic function of AT1(-/-) macrophages versus AT1(+/+).

Conclusions: 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.

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Figures

Figure 1
Figure 1
Macrophages deficient in angiotensin type 1 receptor prevent renal damage-induced increase in atherosclerosis. Representative Oil-Red-O-stained lesions of proximal aorta of mice with intact macrophage angiotensin type 1 receptor (AT1) and sham operation (apoE−/−/AT1+/+→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1+/+→apoE−/− + UNx, n=15) and mice with deficient macrophage AT1 and sham operation (apoE−/−/AT1−/−→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1−/−→apoE−/− + UNx, n=15). Bars in photomicrographs correspond to 250 μm.
Figure 2
Figure 2
Macrophage angiotensin type 1 receptor modulates renal damage-induced macrophage phenotypic change. Immunofluorescent staining for CCR7 (A), iNOS (B), Ym-1 (C) and arginase 1 (E) as fractions of total macrophages stained with CD68 in atherosclerotic lesions of mice with intact macrophage AT1 and sham surgery (apoE−/−/AT1+/+→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1+/+→apoE−/− + UNx, n=15) and mice with deficient macrophage AT1 (apoE−/−/AT1−/−→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1−/−→apoE−/− + UNx, n=15). Bars in photomicrographs correspond to 100 μm.
Figure 3
Figure 3
Macrophages deficient in angiotensin type 1 receptor lessen renal damage-induced increases in apoptosis and ineffective efferocytosis. A. Apoptosis (TUNEL staining). B. Efferocytosis (free-to-macrophage-associated ratio of apoptotic cells). Mice with intact macrophage AT1 and sham surgery (apoE−/−/AT1+/+→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1+/+→apoE−/− + UNx, n=15) and mice with deficient macrophage AT1 and sham surgery (apoE−/−/AT1−/−→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1−/−→apoE−/− + UNx, n=15). Bars in photomicrographs correspond to 100 μm.
Figure 4
Figure 4
Apoptosis and efferocytosis in macrophages with intact or deficient AT1 (AT1+/+, n=3/4; AT1−/−, n=3/4, respectively). A. Apoptotic cells are identified with carboxy-fluorescein diacetate succinimidyl ester [CFDA-SE]/green label. DAPI (blue) staining identifies nuclei. B. CFDA-SE-positive phagocytes as percentage of total macrophages. Bars in photomicrographs correspond to 100 μm.
Figure 5
Figure 5
A. Representative micrograph showing nuclei (Hoechst blue), TUNEL-positive apoptotic cells (red), and macrophages (green) surrounding acellular/anuclear areas in a lesion of apoE−/−/AT1+/+→apoE−/− + UNx. B. Quantitation of necrotic areas assessed by the ratio of acellular/anuclear areas to total atherosclerotic lesion stained by Harris hematoxylin and eosin. Mice with intact macrophage AT1 and sham surgery (apoE−/−/AT1+/+→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1+/+→apoE−/− + UNx, n=15) and mice with deficient macrophage AT1 and sham surgery (apoE−/−/AT1−/−→apoE−/− + Sham, n=10) or uninephrectomy (apoE−/−/AT1−/−→apoE−/− + UNx, n=15). Bars in photomicrographs correspond to 100 μm.
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