Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis

• DOI: 10.1007/s11010-006-9261-0
• Publication Date: 2006-07-12T11:40:26Z
• Authors: Shinji Satoh; Haruki Tanaka; Yasuko Ueda; Jun-ichi Oyama; Masahiro Sugano; Hideki Sumimoto; Yasuo Mori; Naoki Makino
• Keywords: 0301 basic medicine; Rats, Inbred Dahl; Angiotensin II; Heart Ventricles; Myocardium; Apoptosis; Cholinergic Agonists; Calcium Channel Blockers; Transfection; Cell Line; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; Animals, Newborn; GTP-Binding Proteins; Animals; Humans; Carbachol; Myocytes, Cardiac; Calcium Channels; Cells, Cultured; TRPC Cation Channels

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.