Erythropoietin Protects Cardiomyocytes from Cell Death during Hypoxia/Reperfusion Injury through Activation of Survival Signaling Pathways

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.

From cardiac tissue engineering to heart-on-a-chip: beating challenges

“…Cyclic mechanical strain [139], shear stresses [140], and electrical stimulation [20, 141] may also be applied inside the microfluidic chambers to expose cells to cues mimicking those they experience under physiological conditions to promote in vitro tissue maturation. Moreover, hypoxia/normoxia conditions can be set up to mimic normal/pathological conditions [142] and study cell behaviors [142, 143]. …”

Regeneration in the nervous system with erythropoietin

“…During oxidative stress, EPO also preserves neurogenesis (336, 386), stem cell development (126, 220, 237, 312, 372, 387), and promotes erythroid progenitor cell development with the modulation of FoxO3a activity (29, 169, 237, 307). EPO can prevent free radical cell injury (210, 215, 371, 388–390) through the blockade of ROS generation (212, 339, 370, 381, 391). …”

“…In relation to the cardiovascular benefits potentially gained from EPO, several studies suggest that at least high concentrations of EPO may not be warranted to protect cardiac function (142, 168, 407–409). Yet, some work indicates that low concentrations of EPO may be beneficial to the cardiovascular system (212, 360, 410) which could subsequently benefit neurological function.…”

Recombinant Erythropoietin Mitigates Reperfusion Injury in Neonatal Rat Cardiomyocytes by Novel Multiple Signalling Pathways

“…EPO also exerts a neuroprotective effect by attenuating the production of ROS and reducing the basilar artery vasoconstriction on neural, vascular endothelium [20]. m and intracellular Ca 2+ homeostasis via modulation of Akt pathway [21]. Furthermore, it is not known whether EPO has an influence on other factors involved in reperfusion injury, such as caspase activity and cytochrome-c release.…”