Signaling in cardiac hypertrophy has been linked to cholesterol metabolism both through cholesterol precursor mediated post-translational protein modification and cell surface micro-domain mediated signaling complexes. While promising preclinical science has suggested a clear benefit of HMG CoA reductase (statin) therapy for treatment of hypertrophy, the benefit in clinical diastolic heart failure and hypertrophic cardiomyopathy has been less clear. To amplify the pertinent effect of statins seen on hypertrophic signaling, it may be necessary to develop therapies that target more myocardial specific signals downstream from HMG-CoA reductase. The final step of cholesterol synthesis is inhibited by the 24-dehydrocholesterol reductase inhibitor, triparanol. This inhibitor presents an opportunity to study the relative contributions of cholesterol and cholesterol precursors on hypertrophic signaling. In the proposed research, I will evaluate the contribution of cholesterol precursor and cholesterol inhibition on experimental cardiac hypertrophy by both in vivo and in vitro techniques. I will evaluate the effect on hypertrophy at the organ level through detailed in vivo phenotyping. I will also determine effects on the cellular level through measurement of fundamental biophysical properties of isolated cardiomyocytes. Additionally, I will assess the molecular effects of different cholesterol synthesis inhibitors on lipid raft maintenance and signaling protein localization. I will also examine the effect of activation of the cholesterol synthesis pathway through overexpression of cholesterol synthesis enzymes. Together these data may provide novel insights into the interplay of cholesterol synthesis pathway metabolites on the development and maintenance of cardiac hypertrophy. Relevance: Cardiac hypertrophy resulting from hypertension is a common cause of heart failure, which leads to millions of hospitalizations and clinic visits, and billions of dollars in health care expenditures in the US each year. Inhibition of cholesterol metabolism is a potential mechanism to halt the progression of hypertrophy, and thus reduce the burden of heart failure. This research will investigate the specific mechanisms by which cholesterol inhibition may prevent cardiac hypertrophy
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