Abstract
Angiogenesis is critical for re‐establishing the blood supply to the surviving myocardium after myocardial infarction (MI). Long non‐coding RNA ANRIL (lncRNA‐ANRIL) has been reported to regulate endothelial functions in cardiovascular diseases. This study was to determine the role of lncRNA‐ANRIL in Akt regulation and cardiac functions after MI. Human umbilical vein endothelial cells (HUVECs) were exposed to oxygen‐glucose deprivation (OGD) to mimic in vivo ischaemia. The MI model in mice was induced by ligating left anterior descending coronary artery. OGD remarkably decreased lncRNA‐ANRIL expression level, reduced the phosphorylated levels of Akt and eNOS proteins, and inhibited NO release and cell viability, which were duplicated by shRNA‐mediated gene knockdown of lncRNA‐ANRIL. Conversely, all these effects induced by OGD were abolished by adenovirus‐mediated overexpression of lncRNA‐ANRIL in HUVECs. Further, OGD impaired cell migrations and tube formations in HUVECs, which were reversed by lncRNA‐ANRIL overexpression or Akt up‐regulation. RNA immunoprecipitation analysis indicated that the affinity of lncRNA‐ANRIL to Akt protein was increased in OGD‐treated cells. In animal studies, adenovirus‐mediated lncRNA‐ANRIL overexpression increased the phosphorylated levels of Akt and eNOS, promoted post‐ischaemic angiogenesis and improved heart functions in mice with MI surgery. LncRNA‐ANRIL regulates Akt phosphorylation to improve endothelial functions, which promotes angiogenesis and improves cardiac functions in mice following MI. In this perspective, targeting lncRNA‐ANRIL/Akt may be considered to develop a drug to treat angiogenesis‐related diseases.
Highlights
Myocardial infarction (MI) is the leading cause of death in the world.[1]
Our results revealed that ischaemia via reduction of Long non-coding RNA (lncRNA)-ANRIL down-regulates Akt/ eNOS signalling to impair angiogenesis and cardiac functions
We provided the evidences to determine that lncRNA-ANRIL is a regulator of Akt in endothelial cells, and to show that ischaemia via inhibition of lncRNA-ANRIL/Akt/eNOS pathway impairs endothelial cell functions and cardiac functions
Summary
Myocardial infarction (MI) is the leading cause of death in the world.[1]. Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) and, to the recovery of cardiac functions.[2]. Previous studies have indicated that activation of PI3K-Aktdependent signalling improved cardiac functions, reduced infarct size and decreased myocardial apoptosis following MI.[5]. Akt is a serine/threonine kinase regulating essential cellular functions including survival, proliferation, metabolism and patterned gene expression in vascular homeostasis and angiogenesis.[6]. Many of the angiogenic functions attributed to vascular endothelial growth factor are mediated by intracellular activation of Akt signalling.[7]. Whether lncRNA-ANRIL regulates the functions of endothelial cells in angiogenesis after ischaemia is not well-studied. Our results revealed that ischaemia via reduction of lncRNA-ANRIL down-regulates Akt/ eNOS signalling to impair angiogenesis and cardiac functions. In this perspective, targeting lncRNA-ANRIL may be an attractive strategy to improve the prognosis of patients with ischaemia-associated diseases
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