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

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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