miR-27a protects human mitral valve interstitial cell from TNF-α-induced inflammatory injury via up-regulation of NELL-1

Abstract

MicroRNAs (miRNAs) have been reported to be associated with heart valve disease, which can be caused by inflammation. This study aimed to investigate the functional impacts of miR-27a on TNF-α-induced inflammatory injury in human mitral valve interstitial cells (hMVICs). hMVICs were subjected to 40 ng/mL TNF-α for 48 h, before which the expressions of miR-27a and NELL-1 in hMVICs were altered by stable transfection. Trypan blue staining, BrdU incorporation assay, flow cytometry detection, ELISA, and western blot assay were performed to detect cell proliferation, apoptosis, and the release of proinflammatory cytokines. We found that miR-27a was lowly expressed in response to TNF-α exposure in hMVICs. Overexpression of miR-27a rescued hMVICs from TNF-α-induced inflammatory injury, as cell viability and BrdU incorporation were increased, apoptotic cell rate was decreased, Bcl-2 was up-regulated, Bax and cleaved caspase-3/9 were down-regulated, and the release of IL-1β, IL-6, and MMP-9 were reduced. NELL-1 was positively regulated by miR-27a, and NELL-1 up-regulation exhibited protective functions during TNF-α-induced cell damage. Furthermore, miR-27a blocked JNK and Wnt/β-catenin signaling pathways, and the blockage was abolished when NELL-1 was silenced. This study demonstrated that miR-27a overexpression protected hMVICs from TNF-α-induced cell damage, which might be via up-regulation of NELL-1 and thus modulation of JNK and Wnt/β-catenin signaling pathways.

NELL-1 in Genome-Wide Association Studies across Human Diseases

“…38,39 The SNP rs11026076, located in intron 15 of NELL1 gene, was positively associated with cardiovascular mortality with suggestive significance. 38 Meanwhile, in a function study in humans, by Chen et al, 84 NELL-1 protected the mitral valve from inflammatory injury. Another GWAS explored thiazide diureticseinduced QT-interval prolongation.…”

Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis

“…However, no evidence has been reported on the role of microRNAs regulating Wnt signaling during cardiac valve development yet. There are compiling evidence in cardiac valve pathological conditions, such as valvular calcification by miR-29b [ 309 ] and inflammation by miR-27a [ 310 ], as well as in other cardiac pathological conditions such as atrial fibrillation [ 311 ] regulating Wnt3 by miR-27b and ischemia/reperfusion regulating Wnt/β-catenin signaling pathway by miR-148b [ 10 ].…”

Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond

“…Not surprising, Nell-1 gene single-nucleotide polymorphisms has been linked to inflammatory bowel disease (Franke et al 2007) and idiopathic pulmonary fibrosis (Bauer et al 2015). Furthermore, Nell-1 upregulation exhibited protective functions during inflammatory damage in human mitral valve interstitial cells (Chen et al 2018).…”