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

内质网（ER）是公认的参与折叠分泌和膜蛋白的细胞器。内质网通过上调内质网伴侣来应对应激，但长时间和/或过量的内质网应激会导致细胞凋亡。然而，内质网应激在病理生理心脏中的潜在作用尚不清楚。横断主动脉收缩（TAC）后1周和4周，心脏ER伴侣蛋白表达显著升高，表明TAC造成的压力过载导致ER应激延长。TAC在衰竭心脏中激活CHOP-依赖性通路，而不激活jnk或caspase-12-依赖性通路。最后，ER伴侣mRNA水平在心力衰竭患者中显著升高。这些研究结果表明，TAC引起的压力过载可导致内质网应激延长，这可能导致心肌细胞凋亡，在心脏肥厚到衰竭的过程中。泛素-蛋白酶体（U/P）系统参与细胞凋亡的调控。人类衰竭心脏的心肌细胞中泛素化蛋白的显著积累提示心力衰竭的U/P系统受损。由于心肌细胞凋亡有助于压力过载心脏心功能障碍的进展，我们研究了U/P系统在这种情况下的作用。压力过载小鼠心脏的蛋白酶体活性在发生心功能障碍前就已降低。心肌细胞凋亡伴随着蛋白酶体活性的降低和促凋亡/抗凋亡蛋白比值的升高。在培养的心肌细胞中，蛋白酶体的药理抑制积累了促凋亡蛋白，如p53和Bax。通过RNA干扰对这些促凋亡蛋白进行基因沉默，可以阻止相应蛋白的积累，并减轻蛋白酶体抑制引起的心肌细胞凋亡。我们得出结论，蛋白酶体活性的降低有助于心肌细胞凋亡导致的心功能障碍，这是通过降解受损的促凋亡蛋白的积累而引起的。我们现在正在检查衰竭心脏内质网应激和泛素-蛋白酶体系统之间的相互作用。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