Abstract 3466: Potential Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase Inhibition on G Protein-Mediated Cardiac Hypertrophy
Statins have recently been shown to produce anti-cardiac hypertrophic effects via the regulation of small GTPases. 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 (NE)-induced cardiac hypertrophy for its suppressibility of rosuvastatin and the pathways involved by analyzing total protein/DNA content, cell surface area, immunoblotting and RT-PCR for signal transduction molecule. In a concentration-dependent manner, rosuvastatin inhibited total protein synthesis and downregulated basal and NE-induced expression of myosin light chain2 and the c-fos proto-oncogene in cardiomyocytes. Treatment with NE induced cardiac hypertrophy accompanied by Gh expression and membrane translocation. Rosuvastatin inhibited Gh protein activity in cardiomyocytes by inhibiting basal and NE-stimulated mRNA transcription, protein expression and membrane translocation; however, NE-stimulated Gq protein expression was not inhibited. In addition, the NE-stimulated PKC-MEK1,2-ERKs signaling cascade was inhibited by pretreatment with rosuvastatin. Rosuvastatin treatment also helped maintain expression levels of SERCA2a and intracellular calcium concentration. Gh protein is a novel target of statins in myocardial hypertrophy. Statin treatment may directly suppress cardiac hypertrophy through a large Gh-protein-coupled pathway regardless of the regulation of small GTPases.