MECHANICAL STRETCH ACTIVATES A PATHWAY LINKED TO MEVALONATE METABOLISM IN CULTURED NEONATAL RAT-HEART CELLS

It is not certain whether activation of the Ras/mitogen-activated prot ein (MAP) kinase pathway is involved in cardiac hypertrophy. 3-Hydroxy -3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as l ovastatin, prevent farnesylation of the Pas protein, which is critical for Pas's membrane localization and function. Therefore, the present study was undertaken to investigate the role of the Pas pathway, which is linked to mevalonate metabolism, in the mechanism of stretch-induc ed myocyte hypertrophy. Myocytes isolated from 1- to 2-day-old rats we re cultured at 4.1 X 10(6) cells per well in a deformable silicon dish and incubated with serum-free medium for 7 days. The cultures were st retched by 15% on culture day 4. Stretch increased the RNA/DNA ratio b y 20% to 26% on culture days 5 and 6 and the protein/DNA ratio by 18% to 20% on culture days 6 and 7. Stretch accelerated rates of protein s ynthesis by 24% on culture day 6. Stretch increased protein kinase C ( PKC) activity, MAP kinase activity, and c-fos mRNA expression. A selec tive PKC inhibitor, calphostin C (1 X 10(-6) M), prevented the stretch -induced increase in PKC activity, but lovastatin (7.5 X 10(-6) M) did not. Lovastatin as well as calphostin C partially but significantly i nhibited the stretch-induced increases in MAP kinase activity, c-fos m RNA expression, and protein synthesis. Pretreatment with both lovastat in and calphostin C completely inhibited the increases in these variab les caused by stretch. Lovastatin as well as calphostin C prevents str etch-induced cardiac hypertrophy. These results suggest that mechanica l stretch may activate the Pas pathway, which is linked to mevalonate metabolism, in cultured neonatal rat heart cells.