Molecular mechanism of mechanical stress-induced cardiac hypertrophy

压力超负荷状况如高血压导致向心性肥大。相反，容量超负荷状况如二尖瓣反流促进离心性肥大。这些不同的血流动力学负荷导致不同形式的心脏肥大的分子机制尚未完全确定。首先，我们设计并构建了一个独特的计算机控制的实验系统，该系统可以精确控制培养心肌细胞的机械应变以及电起搏。与舒张期应变相比，收缩期应变选择性激活p44/42 MAPK和MEK 1/2。收缩期1小时的应变诱导的[^3H]亮氨酸掺入（24小时）大于舒张期。选择性MEK 1/2抑制剂PD 98059可抑制收缩期菌株[^3H]亮氨酸掺入的增加。接下来，我们使用DNA微阵列技术来确定在人类压力或体积超载心肌中诱导的基因的转录谱。我们在接受心脏手术的患者中使用右心房。根据Swan-Ganz导管压力数据和超声心动图结果将患者分为3组：对照组（n=3）、压力超负荷组（平均右房压> 7 mmHg，n=3）和容量超负荷组（中、重度三尖瓣反流，n=3）。用从上述样品获得的mRNA研究了2，139个人类基因的表达谱。压力超负荷组CDKI-1A和MKP-1基因表达较对照组和容量超负荷组显著增高。这些研究结果表明，在细胞水平上的机械转导可能是心脏压力和容量超负荷之间差异的基础，细胞周期或细胞增殖的抑制因子可能在心脏重塑的病理生理学中起着关键作用。

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.