Abstract
BackgroundEndothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. The molecular mechanism for endothelial dysfunction in the heart is still not clearly understood. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury.Methods and ResultsECs were treated with ischemic insults (lipopolysaccharide and 1% hypoxia) to determine the role of ALKBH5 in ECs angiogenesis. siRNA mediated ALKBH5 gene silencing was used for examining the loss of function. In this study, we report that ALKBH5 levels are upregulated following ischemia and are associated with maintaining ischemia-induced ECs angiogenesis. To decipher the mechanism of action, we found that ALKBH5 is required to maintain eNOS phosphorylation and SPHK1 protein levels. ALKBH5 silencing alone or with ischemic stress significantly increased SPHK1 m6A mRNA methylation. In contrast, METTL3 (RNA methyltransferase) overexpression resulted in the reduced expression of SPHK1.ConclusionWe reported that ALKBH5 helps in the maintenance of angiogenesis in endothelial cells following acute ischemic stress via reduced SPHK1 m6A methylation and downstream eNOS-AKT signaling.
Highlights
Cardiovascular diseases (CVDs) including coronary artery disease, cardiac fibrosis and hypertrophy are the leading cause of deaths world-wide [1, 2]
Our data suggest that acute ischemic stress significantly induced alkB homolog 5 (ALKBH5) expression in endothelial cells
Matrigel tube formation analysis suggests that Endothelial cells (ECs) angiogenesis was preserved till 24 h ischemia (Figures 2A,B)
Summary
Cardiovascular diseases (CVDs) including coronary artery disease, cardiac fibrosis and hypertrophy are the leading cause of deaths world-wide [1, 2]. The physiology of the heart is regulated by multiple factors, including endothelial vascular integrity, endocrine, paracrine and autocrine signaling and epigenetics [3,4,5,6]. Endothelial cells (ECs) dysfunction and its role in promoting coronary artery disease is well-characterized. A wide variety of kinases such as sphingosine kinase-1 (SPHK1), regulate multi-site eNOS phosphorylation, which regulates its subcellular localization and protein-protein interactions [10,11,12]. SPHK1 phosphorylates sphingosine-1, a key extracellular and intracellular messenger which regulates multiple aspects of vascular biology and physiology [13]. Endothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury
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