Abstract
Hypoxia/Reoxygenation (H/R) cardiac injury is of great importance in understanding Myocardial Infarctions, which affect a major part of the working population causing debilitating side effects and often-premature mortality. H/R injury primarily consists of apoptotic and necrotic death of cardiomyocytes due to a compromise in the integrity of the mitochondrial membrane. Major factors associated in the deregulation of the membrane include fluctuating reactive oxygen species (ROS), deregulation of mitochondrial permeability transport pore (MPTP), uncontrolled calcium (Ca2+) fluxes, and abnormal caspase-3 activity. Erythropoietin (EPO) is strongly inferred to be cardioprotective and acts by inhibiting the above-mentioned processes. Surprisingly, the underlying mechanism of EPO's action and H/R injury is yet to be fully investigated and elucidated. This study examined whether EPO maintains Ca2+ homeostasis and the mitochondrial membrane potential (ΔΨm) in cardiomyocytes when subjected to H/R injury and further explored the underlying mechanisms involved. H9C2 cells were exposed to different concentrations of EPO post-H/R, and 20 U/ml EPO was found to significantly increase cell viability by inhibiting the intracellular production of ROS and caspase-3 activity. The protective effect of EPO was abolished when H/R-induced H9C2 cells were treated with Wortmannin, an inhibitor of Akt, suggesting the mechanism of action through the activation Akt, a major survival pathway.
Highlights
Acute myocardial Infarction (AMI) is a major cause of premature mortality in developed countries and is largely associated with Ischemia/Reperfusion (I/R) injury, which is the irreversible damage caused to myocytes during infarction [1]
We for the first time showed the protective effect of EPO in maintaining DYm and intracellular Ca2+ homeostasis in live H9C2 cells, which were subjected to H/R
Our results demonstrate for the first time that the protective effect of EPO in maintaining DYm and intracellular Ca2+ homeostasis in live H9C2 cells, which were subjected to H/R to simulate theconditions of I/R.In our study,the20 U/ml of EPO showed 80% protection of H9C2 cells induced with H/R as compared to 50% protection when treated with 0.4 U/ml or 10 U/ml of EPO [15]
Summary
Acute myocardial Infarction (AMI) is a major cause of premature mortality in developed countries and is largely associated with Ischemia/Reperfusion (I/R) injury, which is the irreversible damage caused to myocytes during infarction [1]. AMI treatments, such as bypass surgery, are inefficient in addressing the symptoms of I/R injury, leading to complications These complications primarily include apoptotic and necrotic cell death in myocytes due to an increase in mitochondrial reactive oxygen species (ROS) and unregulated calcium (Ca2+) fluxes [2]. EPO showed a protective effect in neural cells by maintaining DYm and intracellular Ca2+ concentration under pathological conditions [10] It inhibits caspase-3, 8, 1 like activities and has been shown to protect against apoptosis and necrosis in in-vitro and in-vivo models of brain and spinal cord ischemic injury [11,12,13]
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