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 a lterations in cardiac voltage-gated K+ channels. To investigate mechan isms underlying this K+ channel remodeling, expression of Kv4.2 and Kv 1.4 K+ channel alpha-subunits was examined in cultured newborn rat ven tricular 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 proce ssed, Kv1.4 was significantly diminished while Kv4.2 increased with ti me in culture and became the predominant K+ channel protein. Such K+ c hannel isoform switch from Kv1.4 to Kv4.2 resembles that of the develo pment in vivo. A 72-h treatment with exogenous triiodothyronine (T-3, 0.1 mu M) to cultured neonatal myocytes enhanced the expression of Kv4 .2 by 73% and decreased the Kv1.4 expression by 22%. The effects of T- 3 were associated with an increase in the protein-to-DNA ratio indicat ing myocyte hypertrophy. On the other hand, a 72-h treatment with card iac non-myocyte cell (NMC)-conditioned growth medium (NCGM) or phenyle phrine (20 mu M) induced similar cell hypertrophy, but in sharp contra st to T-3. both markedly suppressed the Kv4.2 channel protein level, I n addition, the trophic and the Kv4.2-downregulating effects of NCGM c ould be mimicked by exogenous endothelin-1 (0.1 mu M), a paracrine fac tor secreted from cardiac NMCs. Our observations for the first time su ggest that cardiac Kv4.2 and Kv1.4 K+ channel alpha-subunits are diffe rentially regulated by a variety of myocardial hypertrophic factors. T hat T-3 accelerated the developmental K+ channel isoform switch from K v1.4 to Kv4.2 in vitro indicates the critical importance of thyroid ho rmone in postnatal K+ channel remodeling. Cardiac NMCs and alpha-adren oceptor activation may contribute to the reduced outward K+ channel de nsity in hypertrophied cardiomyocytes. (C) 1998 Academic Press.