Abstract
Cardiomyocyte senescence is involved in the pathological mechanism of cardiac diseases. Metoprolol is a β1 receptor blocker used for the treatment of hypertension. Recent studies show that Metoprolol can protect cardiomyocytes against ischemia injury. The present study aims to investigate the protective effects of Metoprolol against arginine vasopressin (AVP)-induced cellular senescence in cultured cardiomyocytes. The cell proliferation assay and cytotoxicity lactate dehydrogenase assay showed that the highest tolerated dosage of Metoprolol in H9C2 cardiomyocytes was optimized as 10 µM. The enzyme-linked immunosorbent assay showed that Metoprolol significantly ameliorated the elevated level of the DNA oxidation product 8-hydroxy-2 deoxyguanosine. Metoprolol also decreased the percentage of senescence-associated β-galactosidase positive cells and improved the telomerase activity under AVP exposure. Moreover, treatment with Metoprolol ameliorated the decreased intracellular nicotinamide phosphoribosyltransferase activity, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD+/NADPH) ratio, and Sirtuin1 activity in cardiomyocytes by AVP. Finally, Metoprolol was able to downregulate the AVP-induced expression of acetylated p53 and p21. Taken together, our data reveal that Metoprolol protected the cardiomyocytes from AVP-induced senescence.
Highlights
Pathological cardiac hypertrophy is a compensatory mechanism by which cardiomyocytes adapt to stress overload, which is a high risk for the pathogenesis of the decline of left ventricular function and chronic heart failure [1, 2]
Cell senescence is observed in the cardiac hypertrophy model induced by angiotensin II and in dilated cardiomyopathy caused by the silencing of Bmi1, which is verified by the elevated proportion of SA-β-gal-positive cells [26]
The inhibition of myocyte autophagy was observed in cardiac hypertrophy, proven to be closely related to the activation of oxidative stress [30, 31]
Summary
Pathological cardiac hypertrophy is a compensatory mechanism by which cardiomyocytes adapt to stress overload, which is a high risk for the pathogenesis of the decline of left ventricular function and chronic heart failure [1, 2]. Cardiovascular Toxicology key pathways of cell growth arrest and genome integrity The activation of these factors is the indication of cellular senescence [13]. By blocking the β1 receptor located on the membranes of cardiomyocytes, Metoprolol opposes the excitatory effects at the cardiac level, decreasing blood pressure by lowering both heart rate and systolic output. With this anti-hypertensive property, it can counterbalance an increase of the peripheral vascular resistance mainly dependent on the sympathetic innervation of small arterial myocytes [20]. We investigated the protective effect of Metoprolol against arginine vasopressininduced cell senescence to explore its potential therapeutic property of Metoprolol on pathological cardiac hypertrophy
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