miR‐26a attenuates cardiac apoptosis and fibrosis by targeting ataxia–telangiectasia mutated in myocardial infarction

Abstract

Apoptosis and fibrosis play a vital role in myocardial infarction (MI) induced tissue injury. Although microRNAs have been the focus of many studies on cardiac apoptosis and fibrosis in MI, the detailed effects of miR-26a is needed to further understood. The present study demonstrated that miR-26a was downregulated in ST-elevation MI (STEMI) patients and oxygen-glucose deprivation (OGD)-treated H9c2 cells. Downregulation of miR-26a was closely correlated with the increased expression of creatine kinase, creatine kinase-MB and troponin I in STEMI patients. Further analysis identified that ataxia-telangiectasia mutated (ATM) was a target gene for miR-26a based on a bioinformatics analysis. miR-26a overexpression effectively reduced ATM expression, apoptosis, and apoptosis-related proteins in OGD-treated H9c2 cells. In a mouse model of MI, the expression of miR-26a was significantly decreased in the infarct zone of the heart, whereas apoptosis and ATM expression were increased. miR-26a overexpression effectively reduced ATM expression and cardiac apoptosis at Day 1 after MI. Furthermore, we demonstrated that overexpression of miR-26a improved cardiac function and reduced cardiac fibrosis by the reduced expression of collagen type I and connective tissue growth factor (CTGF) in mice at Day 14 after MI. Overexpression of miR-26a or ATM knockdown decreased collagen I and CTGF expression in cultured OGD-treated cardiomyocytes. Taken together, these data demonstrate a prominent role for miR-26a in linking ATM expression to ischemia-induced apoptosis and fibrosis, key Chiang-Wen Lee and Mao-Shin Lin contributed equally to this work.features of MI progression. miR-26a reduced MI development by affecting ATM expression and could be targeted in the treatment of MI.

The antagonistic effects and mechanisms of microRNA-26a action in hypertensive vascular remodeling

“…Zhang et al showed that miR-26a plays a role in the process of myocardial fibrosis after acute myocardial infarction by inhibiting phosphatase and tensin homolog expression, enhancing matrix metalloproteinase 9 level and promoting the PI3K/AKT pathway (Zhanget al , 2018). Chiang et al discovered that miR-26a ameliorates cardiac dysfunction and fibrosis in myocardial infarction (Chiang et al , 2020). In this study, we first observed that miR-26a expression was downregulated in the thoracic aorta and plasma of SHRs.…”

MicroRNAs in Acute ST Elevation Myocardial Infarction—A New Tool for Diagnosis and Prognosis: Therapeutic Implications

“…miR-26a attenuated cardiac ischemia/reperfusion injury, inflammatory cell infiltration, and cardiomyocyte apoptosis [ 124 , 125 , 126 ]. In a mouse model of MI, the expression of miR-26a was significantly decreased in the infarcted zone of the heart, whereas apoptosis and ATM (ataxia telangiectasia mutated) expression were increased [ 127 ]. The overexpression of miR-26a decreased cardiac apoptosis and fibrosis through repression of ATM, and it was beneficial for the reduction of cardiac dysfunction [ 127 ].…”

“…In a mouse model of MI, the expression of miR-26a was significantly decreased in the infarcted zone of the heart, whereas apoptosis and ATM (ataxia telangiectasia mutated) expression were increased [ 127 ]. The overexpression of miR-26a decreased cardiac apoptosis and fibrosis through repression of ATM, and it was beneficial for the reduction of cardiac dysfunction [ 127 ]. It also improved cardiac function and reduced cardiac fibrosis by lowering the expression of collagen type I and connective tissue growth factor (CTGF) in mice 2 weeks after MI [ 127 , 128 ].…”

The Role of RNA in DNA Breaks, Repair and Chromosomal Rearrangements

“…One example of such complexity is miR-26a that suppressed ATM in glioblastoma cells leading to sensitization of the cells to radiation [84]. However, ATM downregulation by miR-26a was also able to reduce developing myocardial infarction, including ischemia-induced apoptosis and fibrosis, apparently independently of DDR [85]. Yet another miRNA affecting the level of ATM transcripts, as well as radiosensitivity of the cells, also via the 3 -UTR region, was miR-100 in a human glioma cell line M059J [86].…”