Abstract
Cardiovascular diseases are the leading cause of death of death in Taiwan. Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death. Coronary heart disease (CHD) occurs when plaque builds up in the coronary arteries to cause the ischemic heart disease which will enhance myocardial remodeling and also induce myocardial hypoxia. High density lipoprotein (HDL) has been proposed to have cardio-protective effects. Under hypoxic conditions (1%O2 for 24hr), in H9c2 cells, reactive oxygen species (ROS) is induced which leads to cardiomyocyte apoptosis and cardiac dysfunction. Therefore, the present study described the protective effect of HDL on hypoxia-induced cardiomyocyte damage. We investigated the NADPH oxidase-produced ROS-related signaling pathways and apoptosis in cardiomyocytes under hypoxia conditions. Results showed that the ROS mediated cardiac damage might occur via AT1 and PKC activation. Furthermore, hypoxia downregulated the survival protein (p-AKTser473) and anti-apoptotic protein (BCL2), whereas pro-apoptotic protein, Bax and caspase 3 were upregulated. These detrimental effects by ROS and apoptosis were prevented by HDL pretreatment. Our findings revealed the underlying molecular mechanism by which HDL suppresses the hypoxia-induced cardiomyocyte dysfunction. Further, we elucidated the role of HDL on preventing hypoxia induced cardiomyocyte apoptosis is mediated through the inhibition of NADPH oxidase-derived ROS.
Highlights
Atherosclerosis is one of the top ten reasons of death in Taiwan caused due to the accumulation of fatty substances, cholesterol, cellular waste products, calcium and fibrin on the inner coating of artery[1]
We further investigated the effects of High density lipoprotein (HDL) on generation of reactive oxygen species (ROS), a potential factor related to hypoxia-induced H9c2 cells injury, using hydroxyl radical sensitive probe 2’,7’dichlorofluorescein acetoxymethyl ester (DCF-AM), superoxide sensitive probe dihydroethidium (DHE) and MitoSOXTM Red mitochondrial superoxide indicator
The results showed that hypoxia induced superoxide generation was reduced in HDL (25–100μg/ml) pretreated cells, similar results were observed by the treatments with anti-oxidant (NAC, 500 μM) and mitochondrial superoxide inhibitor (Rotenone, 5 μM)
Summary
Atherosclerosis is one of the top ten reasons of death in Taiwan caused due to the accumulation of fatty substances, cholesterol, cellular waste products, calcium and fibrin on the inner coating of artery[1]. Formation of plaques in the arteries could cause chest pain on exertion, and reduces the supply of oxygen to all the parts of body leading to hypoxic condition [2]. Mammalian heart cells cannot generate enough energy to perform essential cellular functions; a continuous supply of oxygen is essential to retain the function and viability of heart [3]. Gene expression is altered by several mechanisms based on the availability of oxygen in the heart which includes the regulation of gene transcription by hypoxia-inducible factor 1α (HIF-1α) [5, 6]. HIF-1α mediates the transcription of many important genes, which can control vital cellular processes like vascular remodeling, metabolism, apoptosis, control of ROS, vasomotor reactivity, and inflammation [7,8,9]
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