Lovastatin prevents stretch- or angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells

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。伸缩性increased RNA/DNA ratio，protein/DNA ratio and rates of protein synthesis.伸缩性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 a3-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…More 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 I D 1 ras D 1 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 I D1 ras ii D1 MAP kinase pathway，which is linked to mevalonate metabolism。Less：Less

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 … More 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