title: Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells.
abstract: Angiotensin II activates p21ras, and mediates cardiac hypertrophic growth through the type 1 angiotensin II receptor in cardiac myocytes. An inhibitor of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase has been shown to block the post-translational farnesylation of p21ras and inhibit protein synthesis in several cell types. Primary cultures of neonatal cardiac myocytes were used to determine whether HMG-CoA reductase inhibitors, lovastatin, simvastatin and pravastatin inhibit the angiotensin II-induced hypertrophic growth. Angiotensin II (10(-6) M) significantly increased protein-DNA ratio, RNA-DNA ratio, ratios of protein synthesis and mitogen-activated protein (MAP) kinase activity. Lipid-soluble HMG-CoA reductase inhibitors, lovastatin (10(-6) M) and simvastatin (10(-6) M) partially and significantly inhibited the angiotensin II-induced increases in these parameters, but a water-soluble HMG-CoA reductase inhibitor, pravastatin (10(-6) M) did not. Mevalonate (10(-4) M) overcame the inhibitory effects of lovastatin and simvastatin on angiotensin II-induced increases in these parameters. A selective protein kinase C inhibitor, calphostin C (10(-6) M) partially and significantly prevented angiotensin II-induced increases in these parameters, and treatment with both lovastatin and calphostin C inhibited completely. Angiotensin II increased p21ras 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 p21ras/MAP kinase pathway, which is linked to mevalonate metabolism.
authors.affiliation: First Department of Internal Medicine, Asahikawa Medical College, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Oi
authors.forename: T
authors.initials: T
authors.lastname: Haneda
authors.forename: J
authors.initials: J
authors.lastname: Osaki
authors.forename: Y
authors.initials: Y
authors.lastname: Kashiwagi
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: J
authors.initials: J
authors.lastname: Kawabe
authors.forename: K
authors.initials: K
authors.lastname: Kikuchi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; D000804:Angiotensin II; D012313:RNA; D004247:DNA; D008148:Lovastatin; D019821:Simvastatin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); C058819:calphostin C; D017035:Pravastatin