The Mechanisms Of Advanced Glycation End Products-induced Cardiomyocytes Aging And The Role Of Pitavastatin

Background:Aging is an inevitable physiological phenomena. People pay more attention to health and longevity with the improvement of living standards. The on-going gerontology research areas focus on the mysteries of aging and anti-aging strategies. In recent years, the aging theories of programmed senescence, telomeres, impaired DNA-repair mechanisms, glycation, free radicals, neuroendocrine mechanisms, somatic mutations and cross-linking are common. The aging theory of glycation is generally accepted by numerous scholars. The advanced glycation end products(AGEs) are products of glycosylation reactions, which continuously accumulate in many tissues or organs of humans and animals with the increase of age. Therefore, it can be used as an important indicator of aging. Several studies have revealed that increase of AGEs occurs with aging hearts, which can induce myocardial remodeling and cardiac diastolic dysfunction resulting in cardiovascular diseases. Oxidative stress plays a very important role in the process of aging. AGEs binding to their receptors, induces the generation of reactive oxidative species(ROS) that can lead to the development of oxidative stress. Mitochondria which are the main target of free radicals, are also a source of ROS. Oxidative stress damages mitochondrial DNA and respiratory chain complexes, which in turn could lead to the production of more free radicals. The mitochondrial function gradually declines with age. In the process of aging, autophagy plays an important role in clearing the damaged macromolecular materials and cell organelles. The level of autophagy declines with age.It has been shown that the moderate activation of autophagy can delay the onset of age-related physiological and pathological phenomena. Oxidative stress and mitochondria damage are closely related to the occurrence of autophagy. So we speculate that oxidative stress, mitochondrial dysfunction, and autophagy may be associated with the AGEs-induced myocardial aging. The foreign researchers have demonstrated that that statins could improve endothelial progenitor cells aging. Pitavastatin is a new inhibitor of HMG-Co A reductase, which can significantly reduce low-density lipoprotein cholesterol and increase high density lipoprotein cholesterol. In addition, pitavastatin plays an important role as an anti-atherosclerotic, anti-oxidant and an anti-inflammatory agent. But the studies on AGEs induced-myocardial cell aging and the effects of pitavastatin are rarely reported. However, conducting studies on the above-mentioned, could be beneficial to delaying myocardial aging.Objective: To investigate the mechanisms of cardiomyocytes aging induced by advanced glycation end-productcs(AGEs) and the protective actions of pitavastatin on AGEs- induced cardiomyocytes aging.Methods: Myocardial cells of neonatal rats were incubated for 48 h with AGEs(100μg/ml), anti-RAGE antibody(1μg/ml) and pitavastatin(600ng/ml). The expressions of p53, p16, p62 and Beclin1 were analyzed using western blot. The senescence-associated beta galactosidase activity(SA-β-Gal) was evaluated via SA-β-Gal assay. Mitochondrial membrane potential and the generation of reactive oxygen species(ROS) were measured through the JC-1 and DCFH-DA.Results: In AGEs group, SA-β-Gal activity and the expressions of p53, p16 and Beclin1 were remarkably increased compared to the control group, but the expression of p62 was significantly decreased. AGEs also markedly decreased mitochondrial membrane potential and significantly increased ROS compared with the control group. After treating with anti-RAGE antibody or pitavastatin, SA-β-Gal activity and the levels of p53,p16 and Beclin1 were markedly decreased compared with AGEs group, but the level of p62 was remarkably increased. In AGEs + anti-RAGE antibody group and AGEs+ pitavastatin group, mitochondrial membrane potential was significantly increased and ROS was remarkably decreased compared with AGEs group.Conclusion: AGEs-RAGE may induce the aging of cardiomyocytes by mitochondrial damage, the generation of ROS, autophagy and pitavastatin could protect the cardiomyocytes aging induced by advanced glycation end products.