Molecular mechanism of mechanical stress-induced cardiac hypertrophy

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Pressure overload conditions such as hypertension result in concentric hypertrophy. Conversely, volume overload conditions such as mitral regurgitation promote an eccentric form of hypertrophy. The molecular mechanism by which these different hemodynamic loads lead to distinct forms of cardiac hypertrophy is incompletely defined. First, we designed and constructed a unique computer-controlled experimental system which allows precisely controlled mechanical strains as well as electrical pacing in cultured cardiomyocytes. Strain in systolic phase selectively activated p44/42 MAPK and MEK1/2 compared with strain in diastolic phase. [^3H]leucine incorporation (24 hr) induced by strain in systolic phase for 1 hr was greater than in diastolic phase. PD98059, a selective inhibitor of MEK1/2, inhibited the increase in [^3H]leucine incorporation by strain in systolic phase. Next, we used DNA microarray technology to define the transcriptional profile of genes induced in human pressure- or volume-overloaded myocardium. We used right atrium in patients who underwent cardiac surgery. On the basis of pressure data of Swan-Ganz catheters and echocardiographic findings, the patients were divided into 3 following groups : control group (n=3), pressure overload group (mean right atrial pressure of > 7 mmHg, n=3) and volume overload group (moderate or severe tricuspid regurgitation, n=3). Expression profiles of 2,139 human genes were investigated with mRNA obtained from the samples above. In the pressure overload group, genes of CDKI-1A and MKP-1 significantly increased compared with those in control or volume overload group. These findings suggest that mechanotransduction at the cellular level may underlie differences between pressure and volume overload of the heart, and that suppressors of cell cycle or cell proliferation may play a critical role in the pathophysiology of cardiac remodeling.