Sajjad Amna, Novoyatleva Tatyana, Vergarajauregui Silvia, Troidl Christian, Schermuly Ralph T, Tucker Haley O, Engel Felix B
Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; Govt. College University Faisalabad, Allama Iqbal Road, Faisalabad 38000, Punjab, Pakistan.
Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany; Division Department of Pulmonary Pharmacotherapy, Justus-Liebig-University Giessen, Aulweg 130, 35392 Giessen, Germany.
Biochim Biophys Acta. 2014 Nov;1843(11):2556-62. doi: 10.1016/j.bbamcr.2014.06.019. Epub 2014 Jul 8.
Apoptosis, or programmed cell death, is an essential physiological process for proper embryogenesis as well as for homeostasis during aging. In addition, apoptosis is one of the major mechanisms causing cell loss in pathophysiological conditions such as heart failure. Thus, inhibition of apoptosis is an important approach for preventive and therapeutic strategies. Here we show that the histone 3 lysine 4- and lysine 36-specific methyltransferase Smyd2 acts as an endogenous antagonistic player of p53-dependent cardiomyocyte apoptosis. Smyd2 protein levels were significantly decreased in cardiomyocytes upon cobalt chloride-induced apoptosis or myocardial infarction, while p53 expression was enhanced. siRNA-mediated knockdown of Smyd2 in cultured cardiomyocytes further enhanced cobalt chloride-induced cardiomyocyte apoptosis. In contrast, Smyd2 overexpression resulted in marked methylation of p53 and prevented its accumulation as well as apoptotic cell death in an Hsp90-independent manner. Moreover, overexpression, of Smyd2, but not Smyd2Y240F lacking a methyl transferase activity, significantly rescued CoCl2-induced apoptosis in H9c2 cardioblasts. Finally, Smyd2 cardiomyocyte-specific deletion in vivo promoted apoptotic cell death upon myocardial infarction, which correlated with enhanced expression of p53 and pro-apoptotic Bax. Collectively, our data indicate Smyd2 as a cardioprotective protein by methylating p53.
细胞凋亡，即程序性细胞死亡，是胚胎正常发育以及衰老过程中维持体内平衡所必需的生理过程。此外，细胞凋亡是导致诸如心力衰竭等病理生理状况下细胞丢失的主要机制之一。因此，抑制细胞凋亡是预防和治疗策略的重要方法。在此，我们表明组蛋白3赖氨酸4和赖氨酸36特异性甲基转移酶Smyd2作为p53依赖性心肌细胞凋亡的内源性拮抗因子发挥作用。在氯化钴诱导的细胞凋亡或心肌梗死后，心肌细胞中Smyd2蛋白水平显著降低，而p53表达增强。在培养的心肌细胞中，siRNA介导的Smyd2敲低进一步增强了氯化钴诱导的心肌细胞凋亡。相反，Smyd2过表达导致p53显著甲基化，并以不依赖热休克蛋白90（Hsp90）的方式阻止其积累以及凋亡性细胞死亡。此外，Smyd2过表达，但缺乏甲基转移酶活性的Smyd2Y240F过表达，显著挽救了H9c2成心肌细胞中氯化钴诱导的凋亡。最后，体内Smyd2心肌细胞特异性缺失促进了心肌梗死后的凋亡性细胞死亡，这与p53和促凋亡蛋白Bax的表达增强相关。总的来说，我们的数据表明Smyd2通过使p53甲基化而成为一种心脏保护蛋白。
