Agonist-independent constitutive activity of angiotensin II receptor promotes cardiac remodeling in mice.

Abstract

The angiotensin II (Ang II) type 1 (AT(1)) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT(1) receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT(1) receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT(1) receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the Gα(q11) subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT(1) receptor is constitutively activated independent of Ang II. As a consequence, AT(1)Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT(1)Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart.

• Authors: Noritaka Yasuda, Hiroshi Akazawa, Kaoru Ito, Ippei Shimizu, Yoko Kudo-Sakamoto, Chizuru Yabumoto, Masamichi Yano, Rie Yamamoto, Yukako Ozasa, Tohru Minamino, Atsuhiko T Naito, Toru Oka, Ichiro Shiojima, Kouichi Tamura, Satoshi Umemura, Pierre Paradis, Mona Nemer, Issei Komuro
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 59 Issue 3 Pg. 627-33 (Mar 2012) ISSN: 1524-4563 [Electronic] United States
• PMID: 22291447 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Agtr1a protein, mouse
• Angiotensin II Type 1 Receptor Blockers
• Benzimidazoles
• Biphenyl Compounds
• Receptor, Angiotensin, Type 1
• Tetrazoles
• RNA
• candesartan

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Biphenyl Compounds
• Blotting, Western
• Disease Models, Animal
• Disease Progression
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism)
• RNA (genetics)
• Receptor, Angiotensin, Type 1 (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tetrazoles (pharmacology)
• Ventricular Dysfunction (genetics, metabolism, physiopathology)
• Ventricular Remodeling (genetics)