Abstract 688: Myocardin is Required to Prevent Mitochondrial Damage and Cardiac Dysfunction in Response to Beta-Adrenergic Receptor Stimulation
Background Myocardin is a transcriptional cofactor of serum response factor and expressed in cardiac myocytes and smooth muscle cells. We have demonstrated that myocardin has a protective role against beta-adrenergic agonist-induced apoptosis in cardiac myocytes in vitro. However, it remains unknown whether myocardin is involved in the progression of heart failure. Therefore, we generated cardiac-specific transgenic mice expressing dominant-negative mutant of myocardin (dnMC-Tg) and investigated postnatal roles of myocardin in the heart under the physiological and pathological conditions.
Methods and Results At 14 weeks of age, cardiac function estimated by echocardiography was not different between dnMC-Tg and non-Tg (NTg) (%FS: 52.8 ± 0.7 vs 54.5 ± 0.7; n.s.), while dnMC-Tg had smaller hearts compared with those of NTg (heart weight/body weight ratio (mg/g): 3.71 ± 0.14 vs 4.51 ± 0.20; p < 0.05). To determine the role of myocardin in the pathological condition, infusion of beta-adrenergic receptor agonist, isoproterenol (ISO, 30 mg/kg/day), was performed. After four-week ISO infusion, left ventricular (LV) wall motion in NTg was hyperkinetic (%FS: 59.1 ± 1.7; p < 0.05), whereas that in dnMC-Tg was significantly reduced (%FS: 45.0 ± 1.2; p < 0.05). In light microscope images, increases in the cross sectional area of cardiac myocyte were observed in both NTg + ISO and dnMC-Tg + ISO groups. Electron microscopy showed mitochondrial swelling and destruction, acompanied by rough and sparse change of myofibrils in hearts from dnMC-Tg + ISO group but not NTg + saline, NTg + ISO, dnMC-Tg + saline groups. Concomitantly with mitochondrial damage, caspase-3 activity in LV wall was significantly increased in dnMC-Tg + ISO group compared with NTg + saline, NTg + ISO, dnMC-Tg + saline groups. Furthermore, in dnMC-Tg + ISO group, cleavage of cardiac troponin T was observed.
Conclusion These findings indicate that myocardin regulates cardiac function through maintaining mitochondrial function and myofibril structure in response to beta-adrenergic receptor stimulation. Myocardin is considered to have pivotal roles in the regulation of developmental heart growth and also the transition from cardiac hypertrophy to heart failure.