title: Rosuvastatin inhibits norepinephrine-induced cardiac hypertrophy via suppression of Gh.
abstract: Statins have recently been shown to produce anti-cardiac hypertrophic effects via the regulation of small GTPases. However, the effects of statins on G protein-mediated cardiac hypertrophy, which is the main pathway of cardiac hypertrophy, have not yet been studied. We sought to evaluate whether statin treatment directly suppresses cardiac hypertrophy through a large G protein-coupled pathway regardless of the regulation of small GTPases. Using neonatal rat cardiomyocytes, we evaluated norepinephrine-induced cardiac hypertrophy for suppressibility of rosuvastatin and the pathways involved by analyzing total protein/DNA content, cell surface area, immunoblotting and RT-PCR for the signal transduction molecule. In a concentration-dependent manner, rosuvastatin inhibited total protein synthesis and downregulated basal and norepinephrine-induced expressions of myosin light chain2 and the c-fos proto-oncogene in cardiomyocytes. Treatment with norepinephrine induced cardiac hypertrophy accompanied by G(h) expression and membrane translocation. Rosuvastatin inhibited G(h) protein activity in cardiomyocytes by inhibiting basal and norepinephrine-stimulated mRNA transcription, protein expression and membrane translocation; however, norepinephrine-stimulated G(q) protein expression was not inhibited. In addition, the norepinephrine-stimulated protein kinase C (PKC)-mitogen-activated protein kinase (MEK 1,2)-extracellular signal-regulated kinases (ERKs) signaling cascade was inhibited by pretreatment with rosuvastatin. Rosuvastatin treatment also helped maintain expression levels of SERCA2a and intracellular calcium concentration. G(h) protein is a novel target of statins in myocardial hypertrophy, and statin treatment may directly suppress cardiac hypertrophy through a large G(h) protein-coupled pathway regardless of the regulation of small GTPases.
authors.affiliation: Cardiology Division, Yonsei Cardiovascular Center, Yonsei University Health System, Seoul 120-752, Republic of Korea.
authors.forename: Eui-Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Byeong-Wook
authors.initials: BW
authors.lastname: Song
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Cha
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eunju
authors.initials: E
authors.lastname: Choi
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Namsik
authors.initials: N
authors.lastname: Chung
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011519:Proto-Oncogenes / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068718:Rosuvastatin Calcium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018994:Myosin Light Chains; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013449:Sulfonamides; C107184:myosin light chain 2; D000068718:Rosuvastatin Calcium; D048049:Extracellular Signal-Regulated MAP Kinases; D024722:Cardiac Myosins; D019204:GTP-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D009638:Norepinephrine