A novel mouse model of lipotoxic cardiomyopathy

Inherited and acquired cardiomyopathies are associated with marked intracel lular lipid accumulation in the heart. To test the hypothesis that mismatch between myocardial fatty acid uptake and utilization leads to the accumula tion of cardiotoxic lipid species, and to establish a mouse model of metabo lic cardiomyopathy, we generated transgenic mouse lines that overexpress lo ng-chain acyl-CoA synthetase in the heart (MHC-ACS). This protein plays an important role in vectorial fatty acid transport across the plasma membrane . MHC-ACS mice demonstrate cardiac-restricted expression of the transgene a nd marked cardiac myocye triglyceride accumulation. Lipid accumulation is a ssociated with initial cardiac hypertrophy, followed by the development of left-ventricular dysfunction and premature death. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cytochrome c rele ase in transgenic hearts suggest that cardiac myocyte death occurs, in part , by lipid-induced programmed cell death. Taken together, our data demonstr ate that fatty acid uptake/utilization mismatch. in the heart leads to accu mulation of lipid species toxic to cardiac myocytes. This novel mouse model will provide insight into the role of perturbations in myocardial lipid me tabolism in the pathogenesis of inherited and acquired forms of heart failu re.