Abstract
Background: Increased cardiac apoptosis is a hallmark of the elderly, which in turn increases the risk for developing cardiac disease. The overexpression of Omi/HtrA2 mRNA and protein contributes to apoptosis in the aged heart. Heat shock factor 1 (HSF1) is a transcription factor that binds to the promoter of Omi/HtrA2 in the aging myocardium. However, whether HSF1 participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether HSF1 plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis.Methods and Results: Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Omi/HtrA2 overexpression in the elderly was negatively correlated with left ventricular function after exercise overload and positively correlated with myocardial Caspase-9 apoptosis. Chromatin immunoprecipitation (ChIP) of aging hearts and plasmid transfection/RNA interference of H9C2 cells revealed that enhancement of HSF1 expression promotes Omi/HtrA2 expression by inducing the promoter activity of Omi/HtrA2 while also increasing mitochondrial apoptosis by upregulating Omi/HtrA2 expression.Conclusions: HSF1 acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while also decreasing cardiac function reserve.
Highlights
IntroductionCardiomyocyte apoptosis increases during aging, which in turn has been shown to be related to decreased cardiac reserve [2] and increased sensitivity to ischemia reperfusion injury [3], stress overload, and other cardiovascular diseases [4]
Aging is a major cardiovascular risk factor [1]
The mouse aging model was constructed using four groups of mice based on ages: 4 months, 12 months, 18 months, and 24 months [13] and evaluated using different classic aging indexes: the mRNA and protein levels of aging-associated proteins p16, p53, and β-galactosidase The results showed that the mRNA levels of p16 and p53 increased with age
Summary
Cardiomyocyte apoptosis increases during aging, which in turn has been shown to be related to decreased cardiac reserve [2] and increased sensitivity to ischemia reperfusion injury [3], stress overload, and other cardiovascular diseases [4]. Whether HSF1 participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether HSF1 plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis. Methods and Results: Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Conclusions: HSF1 acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while decreasing cardiac function reserve
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