Ischaemic preconditioning improves proteasomal activity and increases the degradation of deltaPKC during reperfusion.
Ischaemic preconditioning improves proteasomal activity and increases the degradation of deltaPKC during reperfusion.
复制标题
DOI：
10.1093/cvr/cvp334
复制
发表时间：
2010-01-15
影响因子：
10.8
通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
--
作者：
Churchill EN;Ferreira JC;Brum PC;Szweda LI;Mochly-Rosen D
心肌对缺血损伤的反应受两种高度同源的蛋白激酶C（PKC）同工酶δ和εPKC的调节。在这里，我们确定了这两种同工酶在缺血/再灌注（I/R）和缺血预处理（IPC）的背景下，以更好地了解其在心脏保护中的作用的空间和时间的关系。使用离体大鼠心肌梗死模型，我们发现在长时间缺血事件（IPC）之前的短暂缺血和再灌注使再灌注期间线粒体处的δPKC易位减少3.8倍，εPKC积聚增加16倍。此外，IPC使细胞内δPKC水平下降60 ± 2.7%，而εPKC水平无明显变化。长时间缺血导致ATP依赖性蛋白酶体活性下降48 ± 11%，并使再灌注期间错误折叠蛋白的积累增加192 ± 32%; IPC完全阻止了这两种事件。在IPC过程中，蛋白酶体的药理学抑制或εPKC的选择性抑制恢复了线粒体中的δPKC水平，同时降低了εPKC水平，导致IPC诱导的I/R保护作用丧失。重要的是，增加心肌损伤的部分原因是通过减少促存活信号传导和增加细胞色素c释放到胞质溶胶中来恢复δ PKC介导的I/R促凋亡表型。综上所述，我们的研究结果表明，IPC通过保护ATP依赖的26 S蛋白酶体功能来防止再灌注时的I/R损伤。这减少了促凋亡激酶δPKC在心肌线粒体的蓄积，导致促存活激酶εPKC蓄积。
The response of the myocardium to an ischaemic insult is regulated by two highly homologous protein kinase C (PKC) isozymes, δ and εPKC. Here, we determined the spatial and temporal relationships between these two isozymes in the context of ischaemia/reperfusion (I/R) and ischaemic preconditioning (IPC) to better understand their roles in cardioprotection. Using an ex vivo rat model of myocardial infarction, we found that short bouts of ischaemia and reperfusion prior to the prolonged ischaemic event (IPC) diminished δPKC translocation by 3.8-fold and increased εPKC accumulation at mitochondria by 16-fold during reperfusion. In addition, total cellular levels of δPKC decreased by 60 ± 2.7% in response to IPC, whereas the levels of εPKC did not significantly change. Prolonged ischaemia induced a 48 ± 11% decline in the ATP-dependent proteasomal activity and increased the accumulation of misfolded proteins during reperfusion by 192 ± 32%; both of these events were completely prevented by IPC. Pharmacological inhibition of the proteasome or selective inhibition of εPKC during IPC restored δPKC levels at the mitochondria while decreasing εPKC levels, resulting in a loss of IPC-induced protection from I/R. Importantly, increased myocardial injury was the result, in part, of restoring a δPKC-mediated I/R pro-apoptotic phenotype by decreasing pro-survival signalling and increasing cytochrome c release into the cytosol. Taken together, our findings indicate that IPC prevents I/R injury at reperfusion by protecting ATP-dependent 26S proteasomal function. This decreases the accumulation of the pro-apoptotic kinase, δPKC, at cardiac mitochondria, resulting in the accumulation of the pro-survival kinase, εPKC.
登录
查看更多内容
影响因子：
4.8
作者：
Ling, YH;Liebes, L;Perez-Soler, R
通讯作者：
Perez-Soler, R
DOI：
10.1073/pnas.191369098
发表时间：
2001-09-25
影响因子：
11.1
作者：
Chen, L;Hahn, H;Mochly-Rosen, D
通讯作者：
Mochly-Rosen, D
影响因子：
20.1
作者：
Churchill, EN;Murriel, CL;Szweda, LI
通讯作者：
Szweda, LI
影响因子：
5
作者：
Churchill, Eric N.;Disatnik, Marie-Helene;Mochly-Rosen, Daria
通讯作者：
Mochly-Rosen, Daria
DOI：
10.1152/ajpheart.2001.280.3.h1346
发表时间：
2001-03-01
影响因子：
4.8
作者：
Fryer, RM;Wang, YG;Gross, GJ
通讯作者：
Gross, GJ