Abstract
Long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of cardiovascular diseases, especially in myocardial infarction and ischemia/reperfusion (I/R). However, the underlying molecular mechanism remains unclear. In this study, we determined the role and the possible underlying molecular mechanism of lncRNA-ROR in myocardial I/R injury. H9c2 cells and human cardiomyocytes (HCM) were subjected to either hypoxia/reoxygenation (H/R), I/R or normal conditions (normoxia). The expression levels of lncRNA-ROR were detected in serum of myocardial I/R injury patients, H9c2 cells, and HCM by qRT-PCR. Then, levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) were measured by kits. Cell viability, apoptosis, apoptosis-associated factors, and p38/MAPK pathway were examined by MTT, flow cytometry, and western blot assays. Furthermore, reactive oxygen species (ROS) production was determined by H2DCF-DA and MitoSOX Red probes with flow cytometry. NADPH oxidase activity and NOX2 protein levels were measured by lucigenin chemiluminescence and western blot. Results showed that lncRNA-ROR expression was increased in I/R patients and in H/R treatment of H9c2 cells and HCM. Moreover, lncRNA-ROR significantly promoted H/R-induced myocardial injury via stimulating release of LDH, MDA, SOD, and GSH-PX. Furthermore, lncRNA-ROR decreased cell viability, increased apoptosis, and regulated expression of apoptosis-associated factors. Additionally, lncRNA-ROR increased phosphorylation of p38 and ERK1/2 expression and inhibition of p38/MAPK, and rescued lncRNA-ROR-induced cell injury in H9c2 cells and HCM. ROS production, NADPH oxidase activity, and NOX2 protein levels were promoted by lncRNA-ROR. These data suggested that lncRNA-ROR acted as a therapeutic agent for the treatment of myocardial I/R injury.
Highlights
Myocardial ischemia/reperfusion (I/R) injury leads to adverse cardiovascular outcomes following myocardial ischemia, cardiac surgery or circulatory arrest and is one of the major causes of morbidity and mortality in humans with coronary heart disease [1]
Data indicated that the expression level of lncRNAROR was significantly increased by almost 2 times in the I/R group compared to the normal group (Po0.01, Figure 1A)
LncRNA-ROR expression was increased by approximately 3 times in H9c2 cells and human cardiomyocytes (HCM) after treatment of H/R compared to cells under normoxia (Po0.05, Figure 1B and C)
Summary
Myocardial ischemia/reperfusion (I/R) injury leads to adverse cardiovascular outcomes following myocardial ischemia, cardiac surgery or circulatory arrest and is one of the major causes of morbidity and mortality in humans with coronary heart disease [1]. The underlying molecular mechanisms of myocardial I/R injury are complex and include oxidative stress, intracellular Ca2+ overload, rapid restoration of physiological pH upon reperfusion, mitochondrial permeability transition pore, and exaggerated inflammation [3]. Rapid alterations in ion flux and renormalization of pH following reperfusion causes severe cytotoxicity and I/R injury, characterized by cell death and functional deterioration because of restoration of blood flow [4]. Early restoration of blood flow through the occluded coronary artery might reduce mortality by limiting the infarct size and preserving cardiac function [5,6]. Despite restoration of blood flow, reperfusion alone seems not to be enough to save the myocardium because of the complications that arise from the loss of viability [7]
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