P2Y6 receptor-Galpha12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis.
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.
Nishida
Motohiro
M
Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Sato
Yoji
Y
Uemura
Aya
A
Narita
Yusuke
Y
Tozaki-Saitoh
Hidetoshi
H
Nakaya
Michio
M
Ide
Tomomi
T
Suzuki
Kazuhiro
K
Inoue
Kazuhide
K
Nagao
Taku
T
Kurose
Hitoshi
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis; D005355:Fibrosis; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014530:Uridine Diphosphate / Q000378:metabolism
D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D016212:Transforming Growth Factor beta; C099845:purinoceptor P2Y6; D055513:Connective Tissue Growth Factor; D014530:Uridine Diphosphate; D000255:Adenosine Triphosphate; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D044365:GTP-Binding Protein alpha Subunits, G12-G13