| Summary: | 博士 === 中國醫藥大學 === 臨床醫學研究所博士班 === 104 === Background:
Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. With aging, cardiomyocytes undergo complex changes, which finally result in loss of contractile function and loss of endogenous protection against irreversible injury with hypoxia and aging. Sirt1-FoxO3 transcription may promote autophagy and protect heart from aging injury, which may come from hypoxic injury. It is not clear whether autophagy directly contributes to aging myocardium or is up regulated as an effort to prevent aging process, and, also, the function of FOXO3 regulating autophagy pathway genes in aging cardiomyocytes has not been demonstrated previously.
Aim of study
We aimed to elucidate the effects of the superoxide anion scavenger on cardiac apoptotic and pro-survival pathways in rats with sleep apnea. Second, we investigate the role of Sirt 1 and FoxO3 transcription factor in promoting autophagy and suppress apoptosis in heart during aging.
Method
Experiment one: Forty-two Sprague-Dawley rats at 5–6 month of age were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 month), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2 vs. 21% O2 per 40 s cycle, 8 h per day, 1 month), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O2_-Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3–7% O2 vs. 21% O2 per 40 s cycle, 8 h per day, 1 month). After 1 month, the protein levels and apoptotic cells of excised hearts from three groups were assessed.
Experiment two: Twenty-four SD rats at age four, eight, twelve, and twenty-four month old (n=6 in each group), received echocardiography exam for assessment of cardiac function before sacrifice. The nuclear and cytoplasmic extraction of excised hearts were measured by Western Blotting.
Results
In aging myocardium, we found that aging significantly increased left atrial size, reduced Sirt1 activity in heart, nuclear Sirt1 and FOXO3 levels, decreasing AKT phosphorylation and enhanced ERS after age of eight months. Decline in SIRT1 activity showed significant correlation with left atrial size and functional change of left ventricle of sedentary rats.
Conclusion
This study addressed decreased autophagy activity in rat myocardium in relatively middle lifespan with aging process. Sirt1 activity is important in maintaining cardiac structure and function, avoiding ventricular remodeling. Reversal of reduced Sirt1 activity and ERS in cardiac tissue may be a therapeutic strategy in aging heart.
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