Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal cardiomyocytes

Article

关键词: PROTEIN-KINASE-C;    RAT VENTRICULAR MYOCYTES;    TRANSIENT OUTWARD CURRENT;    ATRIAL-NATRIURETIC-FACTOR;    MYOSIN LIGHT CHAIN-2;    I-TO;    DIFFERENTIAL ACTIVATION;    ELECTRICAL-STIMULATION;    CONTRACTILE ACTIVITY;    CHANNEL EXPRESSION;   

DOI  :  10.1161/01.CIR.0000033970.22130.93

来源: SCIE

【 摘 要 】

Background-Prolonged action potentials (APs) and decreased transient outward K+ currents (I-to) are consistent findings in hypertrophic myocardium. However, the connection of these changes with cardiac hypertrophy is unknown. The present study investigated the effects of changes in I-to and the associated alterations in AP on myocyte hypertrophy induced by phenylephrine. Methods and Results-Chronic incubation of cultured neonatal ventricular rat myocytes (NVRMs) with phenylephrine (PE) reduced I-to density and prolonged AP duration, leading to a 2-fold increase in the net Ca2+ influx per beat and a 1.4-fold increase in Ca2+-transient amplitude. PE treatment of chronically paced (2-Hz) NVRM also induced increases in cell size, protein/DNA ratio, atrial natriuretic factor mRNA expression, as well as beta/alpha myosin mRNA ratio. These hypertrophic changes were associated with a 2.4-fold increase in activation of nuclear factor of activated T-cells (NFAT), indicating increased activity of the Ca2+-dependent phosphatase calcineurin. Overexpression of Kv4.2 channels using adenovirus prevented the AP duration prolongation as well as the increases in Ca2+ influx and Ca2+-transient amplitude induced by PE. Kv4.2 overexpression also prohibited the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic factor expression, beta/alpha myosin mRNA ratio, and NFAT activation. Conclusions-Our results demonstrate that PE-mediated hypertrophy in NRVMs seems to require I-to reductions and AP prolongation associated with increased Ca2+ influx and Ca2+ transients as well as calcineurin activation. The clinical implications of these studies and the possible involvement of other signaling pathways are discussed.

【 授权许可】

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