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

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

Research output: Contribution to journalArticle

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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, P2, 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 languageEnglish (US)
Pages (from-to)2856-2864
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

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Angiotensin Type 1 Receptor
Apolipoproteins E
Atherosclerosis
Macrophages
Kidney
Wounds and Injuries
Atherosclerotic Plaques
Apoptosis
Phenotype
Angiotensin II

Keywords

  • angiotensin ii
  • atherosclerosis
  • kidney
  • macrophages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. / Yamamoto, Suguru; Yancey, Patricia G.; Zuo, Yiqin; Ma, Li Jun; Kaseda, Ryohei; Fogo, Agnes B.; Ichikawa, Iekuni; Linton, MacRae F.; Fazio, Sergio; Kon, Valentina.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 31, No. 12, 12.2011, p. 2856-2864.

Research output: Contribution to journalArticle

Yamamoto, Suguru ; Yancey, Patricia G. ; Zuo, Yiqin ; Ma, Li Jun ; Kaseda, Ryohei ; Fogo, Agnes B. ; Ichikawa, Iekuni ; Linton, MacRae F. ; Fazio, Sergio ; Kon, Valentina. / Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2011 ; Vol. 31, No. 12. pp. 2856-2864.
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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, P2, 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.",
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author = "Suguru Yamamoto and Yancey, {Patricia G.} and Yiqin Zuo and Ma, {Li Jun} and Ryohei Kaseda and Fogo, {Agnes B.} and Iekuni Ichikawa and Linton, {MacRae F.} and Sergio Fazio and Valentina Kon",
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T1 - Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis

AU - Yamamoto, Suguru

AU - Yancey, Patricia G.

AU - Zuo, Yiqin

AU - Ma, Li Jun

AU - Kaseda, Ryohei

AU - Fogo, Agnes B.

AU - Ichikawa, Iekuni

AU - Linton, MacRae F.

AU - Fazio, Sergio

AU - Kon, Valentina

PY - 2011/12

Y1 - 2011/12

N2 - 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, P2, 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.

AB - 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, P2, 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.

KW - angiotensin ii

KW - atherosclerosis

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