| Autor: |
Viola HM; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Australia., Johnstone VPA; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Australia., Cserne Szappanos H; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Australia., Richman TR; The Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, Australia., Tsoutsman T; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.; Sydney Medical School, University of Sydney, Australia., Filipovska A; The Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, Australia., Semsarian C; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.; Sydney Medical School, University of Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Seidman JG; Harvard Medical School, Harvard University, Boston, Massachusetts., Seidman CE; Harvard Medical School, Harvard University, Boston, Massachusetts., Hool LC; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Australia.; Victor Chang Cardiac Research Institute, Sydney, Australia. |
| Abstrakt: |
Heterozygous mice ( αMHC 403/+ ) expressing the human disease-causing mutation Arg403Gln exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of αMHC 403/+ mice with the L-type calcium channel (I Ca-L ) antagonist diltiazem has been shown to decrease left ventricular anterior wall thickness, cardiac myocyte hypertrophy, disarray, and fibrosis. However, the role of the I Ca-L in the development of HCM is not known. In addition to maintaining cardiac excitation and contraction in myocytes, the I Ca-L also regulates mitochondrial function through transmission of movement of I Ca-L via cytoskeletal proteins to mitochondrial voltage-dependent anion channel. Here, the authors investigated the role of I Ca-L in regulating mitochondrial function in αMHC 403/+ mice. Whole-cell patch clamp studies showed that I Ca-L current inactivation kinetics were significantly increased in αMHC 403/+ cardiac myocytes, but that current density and channel expression were similar to wild-type cardiac myocytes. Activation of I Ca-L caused a significantly greater increase in mitochondrial membrane potential and metabolic activity in αMHC 403/+ . These increases were attenuated with I Ca-L antagonists and following F-actin or β-tubulin depolymerization. The authors observed increased levels of fibroblast growth factor-21 in αMHC 403/+ mice, and altered mitochondrial DNA copy number consistent with altered mitochondrial activity and the development of cardiomyopathy. These studies suggest that the Arg403Gln mutation leads to altered functional communication between I Ca-L and mitochondria that is associated with increased metabolic activity, which may contribute to the development of cardiomyopathy. I Ca-L antagonists may be effective in reducing the cardiomyopathy in HCM by altering metabolic activity. |
