| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
The first study was undertaken to investigate the role of the Ras pathway, which is linked to mevalonate metabolism, in the mechanism of stretch-induced myocyte hypertrophy. Stretch increased RNA/DNA ratio, protein/DNA ratio and rates of protein synthesis . Stretch increased protein kinase C (PKC) activity, mitogen-activated protein (MAP) kinase activity and c-fos mRNA expression. A selective PKC inhibitor, calphostin C prevented the stretch-induced increase in PKC activity, but a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, lovastatin did not. Lovastatin as well as calphostin C partially but significantly inhibited the stretch-induced increases in MAP kinase activity, c-fos mRNA expression and protein synthesis. Pretreatment with both lovastatin and calphostin C completely inhibited the increases in these parameters caused by stretch. Lovastatin as well as calphostin C prevents stretch-induced cardiac hypertrophy. These results suggest that mechanical stretch m
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ay activate the Ras pathway, which is linked to mevalonate metabolism, in cultured neonatal rat heart cells.
The second study was undertaken to determine whether HMG-CoA reductase inhibitors, lovastatin, simvastatin and pravastatin inhibit the angiotensin II-induced hypertrophic growth. Angiotensin II significantly increased protein/DNA ratio, RNA/DNA ratio, ratias of protein synthesis and MAP kinase activity. Lipid-soluble HMG-CoA reductase inhibitors, lovastatin and simvastatin partially-and significantly inhibited the angiotensin II-induced increases in these parameters, but a water-soluble HMG-CoA reductase inhibitor, pravastatin did not. Mevalonate overcame the inhibitory effects of lovastatin and simvastatin on angiotensin II-induced increases in these parameters. Calphostin C partically and significantly prevented angiotensin II-induced increases in these parameters, and treatment with both lovastatin and calphostin C inhibited completely. Angiotensin II increased p21ィイD1rasィエD1 activity and membrane association, and lovastatin inhibited them. These studies demonstrate that a lipid-soluble HMG-CoA reductase inhibitor, lovastatin, may prevent angiotensin II-induced cardiac hypertrophy, at least in part, through p21ィイD1rasィエD1 MAP kinase pathway, which is linked to mevalonate metabolism. Less
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