The role of ER stress and ubiquitin-proteasome system in the development of heart failrue

内质网（endoplasmic reticulum，ER）是一种参与折叠分泌蛋白和膜蛋白的细胞器。ER通过上调ER分子伴侣对应激作出反应，但长期和/或过度的ER应激导致细胞凋亡。然而，ER应激在病理生理心脏中的潜在作用仍不清楚。心脏ER分子伴侣的表达显着增加后1周和4周的横向主动脉缩窄（TAC），表明TAC的压力超负荷诱导延长ER应激。TAC在衰竭心脏中激活了CHOP依赖性通路，而非JNK或caspase-12依赖性通路。最后，ER分子伴侣的mRNA水平在衰竭的患者心脏中显著增加。这些结果表明，由TAC的压力超负荷诱导长期的ER应激，这可能有助于心肌细胞凋亡从心肌肥厚到衰竭的进展。泛素-蛋白酶体（U/P）系统参与细胞凋亡的调节， 关于我们 ry蛋白质。人心力衰竭心肌细胞中泛素化蛋白的显著积累提示心力衰竭时U/P系统受损。由于心肌细胞凋亡有助于压力超负荷心脏心功能不全的进展，我们研究了U/P系统在这种情况下的作用。在压力超负荷的小鼠心脏中，蛋白酶体活性在心功能不全发生之前已经被抑制。心肌细胞凋亡沿着蛋白酶体活性降低和促凋亡/抗凋亡蛋白比值升高。在培养的心肌细胞中，药理学抑制蛋白酶体积累促凋亡蛋白，如p53和Bax。通过RNA干扰使这些促凋亡蛋白的基因沉默阻止了各自蛋白的积累，并减弱了蛋白酶体抑制诱导的心肌细胞凋亡。我们的结论是，抑郁症的蛋白酶体活动有助于心功能障碍，导致心肌细胞凋亡，通过积累的促凋亡蛋白受损的降解。我们现在正在检查内质网应激和泛素-蛋白酶体系统在衰竭心脏中的相互作用。少

The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after transverse aortic constriction (TAC), indicating that pressure overload by TAC induced prolonged ER stress. The CHOP-, but not JNK-or caspase-12-, dependent pathway was activated in failing hearts by TAC. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients. These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure. The ubiquitin-proteasome (U/P) system contributes to regulation of apoptosis degrading apoptosis-regulato … More ry proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired U/P system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of U/P system in such conditions. Proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation. We are now checking the interaction between ER stress and ubiquitin-proteasome system in failing hearts. Less