The temporal impact of erythropoietin administration on mitochondrial function and dynamics in cardiac ischemia/reperfusion injury

Juthipong Benjanuwattra; Nattayaporn Apaijai; Titikorn Chunchai; Kodchanan Singhanat; Busarin Arunsak; Kannaporn Intachai; Siriporn C Chattipakorn; Nipon Chattipakorn

doi:10.1016/j.yexmp.2022.104802

The temporal impact of erythropoietin administration on mitochondrial function and dynamics in cardiac ischemia/reperfusion injury

Exp Mol Pathol. 2022 Aug:127:104802. doi: 10.1016/j.yexmp.2022.104802. Epub 2022 Jun 6.

Authors

Juthipong Benjanuwattra¹, Nattayaporn Apaijai², Titikorn Chunchai¹, Kodchanan Singhanat², Busarin Arunsak¹, Kannaporn Intachai², Siriporn C Chattipakorn³, Nipon Chattipakorn⁴

Affiliations

¹ Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand.
² Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
³ Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
⁴ Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: nchattip@gmail.com.

PMID: 35679888
DOI: 10.1016/j.yexmp.2022.104802

Abstract

Erythropoietin (EPO) has been shown to provide protection against ischemia/reperfusion (I/R) injury in various experimental models. However, clinical trials revealed unsatisfactory results when EPO was given to patients with myocardial infarction following reperfusion. The timing of EPO administration and its relation to mitochondrial function may largely involve in this controversy. We hypothesized that EPO given at different time points exert varying cardioprotective effects in terms of myocardial infarct size, left ventricular (LV) function, arrhythmia, apoptosis, mitochondrial function, and mitochondrial dynamics in rats with cardiac I/R injury. Male Wistar rats were subjected to either sham (n = 6) or cardiac I/R operation (n = 48). Rats undergoing cardiac I/R operation (30-min ischemia, followed by 120-min reperfusion) were allotted into 4 subgroups (n = 12/group): vehicle, EPO pretreatment, EPO given during ischemia, and EPO given at reperfusion. EPO was administered intravenously at 5000 unit/kg. Arrhythmia and LV function were monitored throughout the protocol. Next, the hearts were collected to determine infarct size, mitochondrial function, mitochondrial dynamics, gap junction protein, and apoptosis. Cardiac I/R promoted arrhythmias, LV dysfunction, infarct size expansion, apoptosis, mitochondrial dysfunction and increased mitochondrial fission. EPO given either before or during ischemia, but not at reperfusion, attenuated arrhythmia scores, LV dysfunction, infarct size, and apoptosis. Only EPO given either before or during ischemia alleviated mitochondrial swelling, mitochondrial depolarization, and reduced the levels of p-Drp1^ser616/Drp1. Data from in vitro study also confirmed that EPO directly attenuated mitochondrial dysfunction in H9c2 cells subjected to hypoxia/reoxygenation. In conclusion, the EPO administration, either before or during ischemia, exerted cardioprotection against I/R injury by attenuating mitochondrial dynamic imbalance, mitochondrial dysfunction, and apoptosis, leading to reduced infarct size and improved LV function.

Keywords: Apoptosis; Erythropoietin; Mitochondria; Myocardial ischemia; Reperfusion injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Arrhythmias, Cardiac / drug therapy
Arrhythmias, Cardiac / metabolism
Erythropoietin* / pharmacology
Erythropoietin* / therapeutic use
Male
Mitochondria / metabolism
Mitochondrial Dynamics
Myocardial Infarction* / drug therapy
Myocardial Ischemia*
Myocardial Reperfusion Injury* / metabolism
Rats
Rats, Wistar

Substances

Erythropoietin