Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis.
Transient receptor potential (TRP) proteins have been identified as cation channels that are activated by agonist-receptor coupling and mediate various cellular functions. TRPC7, a homologue of TRP channels, has been shown to act as a Ca2+ channel activated by G protein-coupled stimulation and to be abundantly expressed in the heart with an as-yet-unknown function. We studied the role of TRPC7 in G protein-activated signaling in HEK293 cells and cultured cardiomyocytes in vitro transfected with FLAG-tagged TRPC7 cDNA and in Dahl salt-sensitive rats with heart failure in vivo. TRPC7-transfected HEK293 cells showed an augmentation of carbachol-induced intracellular Ca2+ transient, which was attenuated under a Ca2+-free condition or in the presence of SK&F96365 (a Ca2+-permeable channel blocker). Upon stimulation with angiotensin II (Ang II), cultured neonatal rat cardiomyocytes transfected with TRPC7 exhibited a significant increase in apoptosis detected by TUNEL staining, accompanied with a decrease in the expression of atrial natriuretic factor and destruction of actin fibers, as compared with non-transfected cardiomyocytes. Ang II-induced apoptosis was inhibited by CV-11974 (Candesartan; Ang II type 1 [AT1] receptor blocker), SK&F96365, and FK506 (calcineurin inhibitor). In Dahl salt-sensitive rats, apoptosis and TRPC7 expression were increased in the failing myocardium, and a long-term treatment with temocapril, an angiotensin-converting enzyme inhibitor, suppressed both. Our findings suggest that TRPC7 could act as a Ca2+ channel activated by AT1 receptors, leading to myocardial apoptosis possibly via a calcineurin-dependent pathway. TRPC7 might be a key initiator linking AT1-activation to myocardial apoptosis, and thereby contributing to the process of heart failure.
Satoh
Shinji
S
Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan. satoshin@qmed.hosp.go.jp
Tanaka
Haruki
H
Ueda
Yasuko
Y
Oyama
Jun-Ichi
J
Sugano
Masahiro
M
Sumimoto
Hideki
H
Mori
Yasuo
Y
Makino
Naoki
N
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018679:Cholinergic Agonists; D050052:TRPC Cation Channels; C498501:TRPC7 protein, human; D000804:Angiotensin II; D002217:Carbachol; D019204:GTP-Binding Proteins