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MicroRNA-34a Promotes Endothelial Dysfunction and Mitochondrial-Mediated Apoptosis in Murine Models of Acute Lung Injury

Shah, D;Das, P;Alam, MA;Mahajan, N;Romero, F;Shahid, M;Singh, H;Bhandari, V;

Recent evidence has shown that microRNA (miRNAs) are involved in endothelial dysfunction and vascular injury in lung-related diseases. However, the potential role of miR-34a in the regulation of pulmonary endothelial dysfunction, vascular injury and endothelial cells (ECs) apoptosis in acute lung injury (ALI)/acute lung respiratory distress syndrome (ARDS) is largely unknown. Here, we show that miR-34a-5p was up-regulated in whole lungs, isolated ECs from lungs and ECs stimulated with various insults (lipopolysaccharide and hyperoxia). Overexpression of miR-34a-5p in ECs exacerbated endothelial dysfunction, inflammation and vascular injury while the suppression of miR-34a-5p expression in ECs and miR-34a null mutant mice showed protection against lipopolysaccharide (LPS) and hyperoxia-induced ALI. Further, we observed that miR-34a-mediated endothelial dysfunction is associated with decreased miR-34a direct target protein Sirtuin (Sirt)-1 and increased p53 expression in whole lungs and ECs. Mechanistically we show that miR-34a leads to translocation of p53 and Bax to the mitochondrial compartment with disruption of mitochondrial membrane potential to release cytochrome C into the cytosol initiating a cascade of mitochondrial-mediated apoptosis in lungs. Collectively, these data show that downregulating miR-34a expression or modulating its target proteins may improve endothelial dysfunction and attenuate ALI.