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PMID: 19008857 Published · ppublish English Journal Article

P2Y6 receptor-Galpha12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis.

The EMBO journal ·Vol. 27 ·No. 23 ·2008-12-03 ·Pages 3104-15

Nishida M, Sato Y, Uemura A, Narita Y, Tozaki-Saitoh H, Nakaya M, Ide T, Suzuki K, Inoue K, Nagao T, Kurose H

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.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Blood Pressure Cell Adhesion Molecules/biosynthesis Connective Tissue Growth Factor/biosynthesis Fibrosis GTP-Binding Protein alpha Subunits, G12-G13/metabolism Gene Expression Male Mice Mice, Inbred C57BL Mice, Transgenic Myocardium/pathology Myocytes, Cardiac/physiology Peptidyl-Dipeptidase A/biosynthesis Purinergic P2 Receptor Antagonists Rats Receptors, Purinergic P2/physiology Signal Transduction Transforming Growth Factor beta/biosynthesis Uridine Diphosphate/metabolism
Chemicals
Cell Adhesion Molecules POSTN protein, human Purinergic P2 Receptor Antagonists Receptors, Purinergic P2 Transforming Growth Factor beta purinoceptor P2Y6 Connective Tissue Growth Factor Uridine Diphosphate Adenosine Triphosphate ACE protein, human Peptidyl-Dipeptidase A GTP-Binding Protein alpha Subunits, G12-G13
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Nishida Motohiro
Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Sato Yoji
Uemura Aya
Narita Yusuke
Tozaki-Saitoh Hidetoshi
Nakaya Michio
Ide Tomomi
Suzuki Kazuhiro
Inoue Kazuhide
Nagao Taku
Kurose Hitoshi
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.237
Published
2008-12-03
Epub
2008-00-13
Pages
3104-15
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2599880
Subset
IM
External Links
PubMed source DOI: 10.1038/emboj.2008.237 PMC Full Text View journal details
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