Abstract
Cardiomyocyte apoptosis is a common pathological alteration in heart disease which results in systolic dysfunction or sudden death. Klotho is a novel anti-aging hormone. We tested the effects of klotho on cell apoptosis in isoproterenol-treated cardiomyocytes. In BALB/c mice, cardiac injury was induced by subcutaneous injection of isoproterenol (5mg/kg, for 9days, sc). Klotho (0.01 mg/kg, every other day for 4days, ip) was administered to determine the changes in isoproterenol-induced apoptosis. Mouse heart was harvested at day 2, day 5, and day 9 after isoproterenol injection. Isoproterenol induced cardiac apoptosis and endoplasmic reticulum (ER) stress in a time-dependent manner. However, klotho partly reversed isoproterenol-induced cardiac apoptosis and ER stress. These same effects were observed in cultured cardiomyocytes. Furthermore, the results also showed that SB203580, a p38 inhibitor, and SP600125, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduced cardiomyocyte apoptosis and ER stress, however, klotho suppressed isoproterenol-induced activation of p38 and JNK. Taken together, these results indicated that cardioprotection by klotho was related to the attenuation of ER stress and ER stress-induced apoptosis, at least partly, through suppressing activation of the p38 and JNK pathway.
Highlights
Regardless of etiology, cardiac remodeling is a common pathological alteration in terms of structure and function in response to various pathogenic stimuli including chronic pressure overload, chronic volume overload, and myocardial infarction[1]
The levels of GRP78, HSP47 and CHOP were significantly decreased by klotho, SB203580 and SP600125, but not by PD98059 (Figure 10 C, D, E, F).These results suggested that klotho ameliorated Endoplasmic reticulum (ER) stress and ER stress-induced apoptosis through inhibition of the p38 and Jun NH2-terminal kinase (JNK) pathway
Klotho partly inhibited phosphorylation of the p38 and JNK pathway in H9c2 cells. so we concluded that klotho inhibited ISO-induced ER stress and apoptotic signal through suppression of the P38 and JNK pathway, and improved cardiac pathological changes
Summary
Regardless of etiology, cardiac remodeling is a common pathological alteration in terms of structure and function in response to various pathogenic stimuli including chronic pressure overload (e.g. essential hypertension), chronic volume overload (e.g. valvular regurgitation), and myocardial infarction[1]. Reports demonstrate that upregulation of ER chaperone proteins and subsequent transcription induction of pro-apoptosis transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP / GADD153) are involved in ER stress-mediated apoptosis induced by pathogenic stimuli including isoproterenol (ISO) in cultured cardiomyocytes [3,9,10,11]. Mitogen-activated protein kinases (MAPK), an ubiquitous intracellular signal, consisting of extracellular signal regulated kinase 1/2 (ERK1/2), p38 and c-Jun NH2terminal kinase (JNK), regulates cellular proliferation, differentiation and apoptosis, and plays an important regulatory role in ER stress-induced apoptosis[14,17,18]. Accumulative evidence indicates that secreted klotho exerts resistance to oxidative stress and inflammation via regulation of intracellular signal pathways including p38 MAPK [21,22]. We investigated the protective effect of klotho on ER stress and subsequent apoptosis regulated by the MAPK signaling pathway
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