The mechanism of senescence in cardiomyocytes and application of a therapeutic approach for heart failure

细胞衰老是细胞功能下降的重要现象。最近的研究表明，氧化应激可在短时间内诱导增殖细胞的衰老。这种现象被称为早衰。然而，目前尚不清楚是否也能在心肌细胞中诱导早衰。本研究的目的是研究是否可以通过阿霉素(DOX)模拟氧化应激在心肌细胞中诱导衰老样表型。老年大鼠(24月龄)心肌细胞衰老相关β-半乳糖苷酶(SA b-GAL)染色显著增强，细胞周期蛋白依赖性激酶抑制物(CDK-IS)、p27^-lt；kip1&gt；和p16^&lt；INK4a&gt；蛋白或RNA水平升高。老年心肌细胞的心肌肌钙蛋白I磷酸化和端粒酶活性也降低。培养新生鼠卡…的治疗2‘，7’-二氯二乙酸二氯荧光素染色证实，低浓度DOX(10^&lt；-7&gt；mo1/L)可诱导更多的心肌细胞发生氧化应激，但不能诱导细胞凋亡。在DOX处理的新生心肌细胞中，随着年龄的增长，SA b-Gal、CDK-I表达的阳性染色增加，心肌肌钙蛋白I磷酸化减少，端粒酶活性降低。DOX处理的新生心肌细胞(下调：A-MHC，GATA4，NKX2.5，上调：ANP，血管紧张素II受体)可观察到衰老细胞中典型的mRNA表达的变化。我们还发现，PML蛋白和乙酰化P53是参与应激诱导增殖细胞过早衰老的关键蛋白，它们与DOX处理的心肌细胞衰老的细胞变化有关。综上所述，DOX处理的心肌细胞表现出与老年大鼠心肌细胞相似的特征性变化。PML相关的P53乙酰化可能是心肌细胞衰老样改变的一个潜在机制。这些发现表明了氧化应激引起心肌功能障碍的新机制。较少

Cellular senescence is an important phenomenon in decreased cellular function. Recently, it was shown that cellular senescence is induced in proliferating cells within a short period of time by oxidative stresses. This phenomenon is known as premature senescence. However, it is still unknown whether premature senescence can be also induced in cardiomyocytes. The aim of the present study was to investigate whether a senescence-like phenotype can be induced in cardiomyocytes by simulating oxidative stress with doxorubicin (DOX). In cardiomyocytes obtained from aged rats (24 months of age), the staining for senescence-associated b-galactosidase (SA b-gal) increased significantly and the protein or RNA lelvels of cyclin-dependent kinase inhibitors (cdk-Is) p21^<cip1/waf1>, p27^<kip1> andp16^<INK4a> increased compared to those of young rats. Decreased cardiac troponin I phosphorylation and telomerase activity were also observed in aged cardiomyocytes. Treatment of cultured neonatal rat card … More iomyocytes with a low concentration of DOX (10^<-7>mol/L) did not induce apoptosis but did induce oxidative stress, which was confirmed by 2', 7'-dichlorofluorescin diacetate staining. In DOX-treated neonatal cardiomyocytes, increased positive staining for SA b-gal, cdk-I expression, decreased cardiac troponin I phosphorylation, and decreased telomerase activity were observed, as aged cardiomyocytes. Alterations in mRNA expression typically seen in aged cells were observed in DOX-treated neonatal cardiomyocytes (downregulation : a-MHC, GATA4, Nkx2.5, upregulation : ANP, angiotensin II receptor). We also found that PML protein and acetylated p53, key proteins involved in stress-induced premature senescence in proliferating cells, were associated with cellular alterations of senescence in DOX-treated cardiomyocytes. In conclusion, cardiomyocytes treated with DOX showed characteristic changes similar to cardiomyocytes of aged rats. PML-related p53 acetylation may be an underlying mechanism of senescence-like alterations in cardiomyocytes. These findings indicate a novel mechanism of myocardial dysfunction induced by oxidative stress. Less