P2Y6 Receptor-Galpha12/13 Signalling in Cardiomyocytes Triggers Pressure Overload-induced Cardiac Fibrosis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2008 Nov 15

PMID 19008857

Citations 83

Authors

Motohiro Nishida

Yoji Sato

Aya Uemura

Yusuke Narita

Hidetoshi Tozaki-Saitoh

Michio Nakaya

Tomomi Ide

Kazuhiro Suzuki

Kazuhide Inoue

Taku Nagao

Hitoshi Kurose

Affiliations

Soon will be listed here.

Abstract

Cardiac fibrosis, characterized by excessive deposition of extracellular matrix proteins, is one of the causes of heart failure, and it contributes to the impairment of cardiac function. Fibrosis of various tissues, including the heart, is believed to be regulated by the signalling pathway of angiotensin II (Ang II) and transforming growth factor (TGF)-beta. Transgenic expression of inhibitory polypeptides of the heterotrimeric G12 family G protein (Galpha(12/13)) in cardiomyocytes suppressed pressure overload-induced fibrosis without affecting hypertrophy. The expression of fibrogenic genes (TGF-beta, connective tissue growth factor, and periostin) and Ang-converting enzyme (ACE) was suppressed by the functional inhibition of Galpha(12/13). The expression of these fibrogenic genes through Galpha(12/13) by mechanical stretch was initiated by ATP and UDP released from cardiac myocytes through pannexin hemichannels. Inhibition of G-protein-coupled P2Y6 receptors suppressed the expression of ACE, fibrogenic genes, and cardiac fibrosis. These results indicate that activation of Galpha(12/13) in cardiomyocytes by the extracellular nucleotides-stimulated P2Y(6) receptor triggers fibrosis in pressure overload-induced cardiac fibrosis, which works as an upstream mediator of the signalling pathway between Ang II and TGF-beta.

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