抄録
Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and systolic dysfunction, which often leads to severe heart failure and sudden death. However, little is known about the pathogenic mechanism for DCM, and no therapeutical method is established at present except for cardiac transplantation. We created a knock-in mouse model of DCM caused by a deletion mutation δK210 in cardiac troponin T and explored its molecular pathogenic process and potential pharmacotherapy. Mutant mice developed enlarged hearts with bi-ventricular dilation and systolic dysfunction and suffered sudden death frequently, recapitulating human DCM with this mutation. Skinned cardiac muscle fibers from mutant mice showed a decreased Ca2+ sensitivity of force generation, confirming our previous hypothesis that decreased contractility of cardiac muscle is a primary pathogenic mechanism of this mutation. Surprisingly, however, intact cardiac muscle fibers from mutant mice showed no significant reduction in isometric force per cross-sectional area. Analyses of Fura-2 loaded cardiomyocytes revealed that this was due to an increase in the amplitude of intracellular Ca2+ transient. Biochemical analyses, including DNA microarray, strongly suggested that Ca2+ transient was increased through down-regulation of a specific isoform of phosphodiesterase (PDE4B) and associated increase in cAMP in cardiomyocytes of mutant mice, which could compensate for the decreased myofilament Ca2+ sensitivity but at the same time would increase the risk for arrhythmia leading to sudden death due to a Ca2+ overload. [J Physiol Sci. 2006;56 Suppl:S53]
