Role of Ion Channels and Exchangers in Mechanical Stretch–Induced Cardiomyocyte Hypertrophy

From the Department of Medicine III (T.Y., I.K., S.K., Y.Z., R.A., H.U., Y.Y.), University of Tokyo School of Medicine, Tokyo, Japan; the Health Service Center (T.Y.), University of Tokyo, Tokyo, Japan; and the Second Department of Medicine (R.N.), Gumma University, Gumma, Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Medicine III, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.ac.jp

Abstract—We have previously reported that stretching of cardiomyocytes activates the phosphorylation cascade of protein kinases, including Raf-1 kinase and mitogen-activated protein (MAP) kinases, followed by an increase in protein synthesis partly through enhanced secretion of angiotensin II and endothelin-1. Membrane proteins, such as ion channels and exchangers, have been postulated to first receive extracellular stimuli and evoke intracellular signals. The present study was performed to determine whether mechanosensitive ion channels and exchangers are involved in stretch-induced hypertrophic responses. Neonatal rat cardiomyocytes cultured on expandable silicone dishes were stretched after pretreatment with a specific inhibitor of stretch-sensitive cation channels (gadolinium and streptomycin), of ATP-sensitive K⁺ channels (glibenclamide), of hyperpolarization-activated inward channels (CsCl), or of the Na⁺-H⁺ exchanger (HOE 694). Pretreatment with gadolinium, streptomycin, glibenclamide, and CsCl did not show any inhibitory effects on MAP kinase activation by mechanical stretch. HOE 694, however, markedly attenuated stretch-induced activation of Raf-1 kinase and MAP kinases by 50% and 60%, respectively, and attenuated stretch-induced increase in phenylalanine incorporation into proteins. In contrast, HOE 694 did not inhibit angiotensin II–and endothelin-1–induced Raf-1 kinase and MAP kinase activation. These results suggest that among many mechanosensitive ion channels and exchangers, the Na⁺-H⁺ exchanger plays a critical role in mechanical stress–induced cardiomyocyte hypertrophy.

Key Words: mechanosensitive ion channel • Na⁺-H⁺ exchanger • Raf-1 kinase • mitogen-activated protein kinase

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