Downregulation and nuclear relocation of MLP during the progression of right ventricular hypertrophy induced by chronic pressure overload

The cardiac LIM domain protein MLP plays a crucial role in the architecture and mechanical function of cardiac myocytes. Mice lacking the MLP gene dev elop cardiac hypertrophy, dilated cardiopathy and heart failure. We investi gated whether downregulation of MLP is induced by pressure overload and con tributes to the physiopathology of cardiac hypertrophy and failure. We stud ied this mechanism in rat right ventricles submitted to pulmonary arterial hypertension, because it is known that this ventricle is very vulnerable to the deleterious effects of pressure overload. During the progression of ca rdiac hypertrophy to failure over a 31 days period there was a dramatic dec rease by 50% of the MLP transcripts level. Consistently, immunohistochemist ry detected very weak protein signals in the cytoplasms of cardiomyocytes a t the failing stage, but myocytes nuclei were heavily labeled. The nuclear relocation was confirmed by the immunodetection of MLP on the nuclear and c ytosolic fractions. This nuclear localization is the hallmark of a retro-di fferentiated phenotype, since it has been observed only in differentiating myoblasts. These changes were associated with ultrastructural disorganizati on of the myofibrils similar to that observed in MLP -/- mice. Therefore, M LP dowregulation occurring during gene reprogramming may critically contrib ute to mechanical failure of the myocardium. (C) 2000 Academic Press.