Regulation of Kv4.2 and Kv1.4 K+Channel Expression by Myocardial Hypertrophic Factors in Cultured Newborn Rat Ventricular Cells

Postnatal development and myocardial hypertrophy are associated with alterations in cardiac voltage-gated K+channels. To investigate mechanisms underlying this K+channel remodeling, expression of Kv4.2 and Kv1.4 K+channelα-subunits was examined in cultured newborn rat ventricular myocytes by Western blot analysis using polyclonal antibodies against each of the subunits. At day 5 of cell culture, Kv1.4 protein was expressed at higher level than Kv4.2; as the age of culture progressed, Kv1.4 was significantly diminished while Kv4.2 increased with time in culture and became the predominant K+channel protein. Such K+channel isoform switch from Kv1.4 to Kv4.2 resembles that of the developmentin vivo.A 72-h treatment with exogenous triiodothyronine (T3, 0.1μm) to cultured neonatal myocytes enhanced the expression of Kv4.2 by 73% and decreased the Kv1.4 expression by 22%. The effects of T3were associated with an increase in the protein-to-DNA ratio indicating myocyte hypertrophy. On the other hand, a 72-h treatment with cardiac non-myocyte cell (Nmc)-conditioned growth medium (NCGM) or phenylephrine (20μm) induced similar cell hypertrophy, but in sharp contrast to T3, both markedly suppressed the Kv4.2 channel protein level. In addition, the trophic and the Kv4.2-downregulating effects of NCGM could be mimicked by exogenous endothelin-1 (0.1μm), a paracrine factor secreted from cardiac Nmcs. Our observations for the first time suggest that cardiac Kv4.2 and Kv1.4 K+channelα-subunits are differentially regulated by a variety of myocardial hypertrophic factors. That T3accelerated the developmental K+channel isoform switch from Kv1.4 to Kv4.2in vitroindicates the critical importance of thyroid hormone in postnatal K+channel remodeling. Cardiac Nmcs andα-adrenoceptor activation may contribute to the reduced outward K+channel density in hypertrophied cardiomyocytes.