Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ.
Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE((-/-)) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser(1177)-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE((-/-)) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser(1177)-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD.
Division of Cardiology, Department of Medicine, Emory UniversityAtlanta, Georgia, USA; Cardiac Regeneration Research Institute, Wenzhou Medical UniversityWenzhou 325035, China.
Ming
M
Li
Division of Cardiology, Department of Medicine, Emory University Atlanta, Georgia, USA.
Thor
T
Tejada
Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University Atlanta, Georgia, USA.
Jonathan P
JP
Lambert
Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University Atlanta, Georgia, USA.
Chad K
CK
Nicholson
Division of Cardiology, Department of Medicine, Emory University Atlanta, Georgia, USA.
Eiji
E
Yahiro
Division of Cardiology, Department of Medicine, Emory University Atlanta, Georgia, USA.
Vats T
VT
Ambai
Division of Cardiology, Department of Medicine, Emory University Atlanta, Georgia, USA.
Syeda F
SF
Ali
Department of Medicine, University of Alabama at Birmingham Birmingham, Alabama, USA.
Eddie W
EW
Bradley
Victor Chang Cardiac Research Institute Darlinghurst, NSW 2010, Australia.
Robert M
RM
Graham
Department of Medicine, University of Alabama at BirminghamBirmingham, Alabama, USA; VA Medical CenterBirmingham, Alabama, USA.
Louis J
LJ
Dell'Italia
Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University Atlanta, Georgia, USA.
John W
JW
Calvert
Division of Cardiology, Department of Medicine, Emory University Atlanta, Georgia, USA.
Nawazish
N
Naqvi
AT2R; PPAR-γ; angiotensin II; apoE(-/-); blood pressure; eNOS
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