Insulin-like growth factor-induced hypertrophy of cultured adult rat cardiomyocytes is L-type calcium-channel-dependent.

Abstract

The insulin-like growth factors-I and -II are potent growth stimulators in vivo and for many different cultured cells in vitro. Here IGF-I and -II are shown to directly induce hypertrophy of adult rat ventricular cardiomyocytes in serum-free medium as demonstrated by their increased size, total protein synthesis, and transcription of muscle-specific genes. The cells hypertrophied within 1 day when exposed to as little as 10(-11) M IGF-I or 10(-10) M IGF-II. With 10(-8) M IGF-I, cell size was significantly increased 34% by 1 day of culture and 57% by 2 days. With 10(-8) M IGF-II, cell size was similarly increased 32% by day 1 and 57% by 2 days. During hypertrophy, total protein synthesis was increased 2.3-fold with IGF-I and 2-fold with IGF-II. Gene expression for myosin light chain 2 and troponin I was upregulated with either growth factor. Hypertrophy induced by IGF-I was blocked by IGF binding protein-3, which binds IGF-I, while that induced by IGF-II was blocked by antibodies against IGF-II. Nicardipine, an inhibitor of L-type Ca2+-channels, completely blocked the hypertrophy induced by either IGF showing for the first time that such voltage-dependent channels are necessary for the hypertrophic effects of the IGFs on adult cardiomyocytes.