Depre Christophe, Wang Qian, Yan Lin, Hedhli Nadia, Peter Pallavi, Chen Li, Hong Chull, Hittinger Luc, Ghaleh Bijan, Sadoshima Junichi, Vatner Dorothy E, Vatner Stephen F, Madura Kiran
Department of Cell Biology & Molecular Medicine, UMDNJ, Newark, NJ 07103, USA.
Circulation. 2006 Oct 24;114(17):1821-8. doi: 10.1161/CIRCULATIONAHA.106.637827. Epub 2006 Oct 16.
The adaptation of cardiac mass to hemodynamic overload requires an adaptation of protein turnover, ie, the balance between protein synthesis and degradation. We tested 2 hypotheses: (1) chronic left ventricular hypertrophy (LVH) activates the proteasome system of protein degradation, especially in the myocardium submitted to the highest wall stress, ie, the subendocardium, and (2) the proteasome system is required for the development of LVH.
Gene and protein expression of proteasome subunits and proteasome activity were measured separately from left ventricular subendocardium and subepicardium, right ventricle, and peripheral tissues in a canine model of severe, chronic (2 years) LVH induced by aortic banding and then were compared with controls. Both gene and protein expressions of proteasome subunits were increased in LVH versus control (P<0.05), which was accompanied by a significant (P<0.05) increase in proteasome activity. Posttranslational modification of the proteasome was also detected by 2-dimensional gel electrophoresis. These changes were found specifically in left ventricular subendocardium but not in left ventricular subepicardium, right ventricle, or noncardiac tissues from the same animals. In a mouse model of chronic pressure overload, a 50% increase in heart mass and a 2-fold increase in proteasome activity (both P<0.05 versus sham) were induced. In that model, the proteasome inhibitor epoxomicin completely prevented LVH while blocking proteasome activation.
The increase in proteasome expression and activity found during chronic pressure overload in myocardium submitted to higher stress is also required for the establishment of LVH.
心脏质量适应血流动力学过载需要蛋白质周转的适应，即蛋白质合成与降解之间的平衡。我们测试了两个假设：（1）慢性左心室肥厚（LVH）激活蛋白质降解的蛋白酶体系统，特别是在承受最高壁应力的心肌中，即心内膜下，以及（2）蛋白酶体系统是LVH发展所必需的。
在主动脉缩窄诱导的严重慢性（2年）LVH犬模型中，分别测量左心室心内膜下和心外膜下、右心室及外周组织中蛋白酶体亚基的基因和蛋白质表达以及蛋白酶体活性，然后与对照组进行比较。与对照组相比，LVH组蛋白酶体亚基的基因和蛋白质表达均增加（P<0.05），同时蛋白酶体活性显著增加（P<0.05）。二维凝胶电泳也检测到蛋白酶体的翻译后修饰。这些变化特异性地出现在左心室心内膜下，而在同一动物的左心室心外膜下、右心室或非心脏组织中未发现。在慢性压力过载的小鼠模型中，心脏质量增加50%，蛋白酶体活性增加2倍（与假手术组相比，均P<0.05）。在该模型中，蛋白酶体抑制剂环氧霉素在阻断蛋白酶体激活的同时完全阻止了LVH。
在承受更高应力的心肌慢性压力过载期间发现的蛋白酶体表达和活性增加也是LVH建立所必需的。
