Role of miR‐185‐5p as modulator of periostin synthesis and smooth muscle contraction in asthma

Abstract

Asthma is a chronic respiratory disease produced by an aberrant immune response that originates with breathing difficulties and cough, through airway remodeling. The above pathophysiological events of asthma emerge the regulators of effectors, like epigenetics, which include microRNAs (miRNAs) who perform post-transcriptional regulation, controlling diverse pathways in respiratory diseases. The objective of the study was to determine how miR-185-5p regulates the secretion of periostin by airway structural cells, and smooth muscle cells contraction, both related to airway remodeling in asthma. We used miR-185-5p mimic and inhibitors in bronchial smooth muscle cells (BSMCs) and small airway epithelial cells (SAECs) from healthy subjects. Gene expression and protein levels of periostin (POSTN), CDC42, and RHOA were analyzed by RT-PCR and ELISA/Western blot, respectively. BSMC contractility was analyzed using cell-embedded collagen gels and measurement of intracellular calcium was performed using Fura-2. Additionally, miR-185-5p and periostin expression were evaluated in sputum from healthy and asthmatics. From these experiments, we observed that miR-185-5p modulation regulates periostin mRNA and protein in BSMCs and SAECs. A tendency for diminished miR-185-5p expression and higher periostin levels was seen in sputum cells from asthmatics compared to healthy, with an inverse correlation observed between POSTN and miR-185-5p. Inhibition of miR-185-5p produced higher BSMCs contraction induced by histamine. Calcium mobilization was not modified by miR-185-5p, showing that miR-185-5p role in BSMC contractility is performed by regulating CDC42 and RhoA procontractile factors instead. In conclusion, miR-185-5p is a modulator of periostin secretion by airway structural cells and of smooth muscle contraction, which can be related to asthma pathophysiology, and thus, might be a promising therapeutic target.

MiR-185-5p measurement assists in reflecting Th1/Th2 cell imbalance, inflammatory cytokine production, and exacerbation risk for childhood asthma

“…A potential reason would be that, as discussed above, miR-185-5p could contribute to aggravated inflammation, Th1/ Th2 imbalance, lung damage, etc., hence, exacerbating childhood asthma. 14,15,19,30 As a result, miR-185-5p was correlated to exacerbation risk in childhood asthma patients. Notably, miR-185-5p regulates periostin synthesis and smooth muscle contraction to participate in the pathology of asthma.…”

“…The potential reasons would be as follows: (1) miR-185-5p could trigger the imbalance of Th1/Th2 cells and aggravate the inflammation, leading to the onset of childhood asthma 14,15 and (2) miR-185-5p could also modulate the perisynthesis and smooth muscle contraction to induce childhood asthma, 19 thus, miR-185-5p could reflect higher childhood asthma susceptibility.…”

“…Importantly, this study also disclosed that miR-185-5p was positively correlated with exacerbation severity in childhood asthma patients. The possible arguments would be that: (1) as discussed above, miR-185-5p could induce immune imbalance and aggravate inflammation, contributing to the exacerbation of childhood asthma, 14,15 (2) miR-185-5p might also modulate the protein secretion and smooth muscle contraction to aggravate childhood asthma, 19 (3) miR-185-5p could regulate apoptosis and necroptosis in alveolar type II cells, which might further exacerbate lung damage. 30 Taken together, a positive association was observed between miR-185-5p and exacerbation severity in childhood asthma patients.…”

“…15 Notably, the role of miR-185-5p in the pathophysiology of asthma is also revealed by a study, which discovers that miR-185-5p regulates periostin synthesis and smooth muscle contraction to accelerate asthma. 19 Based on the above evidence, it could be speculated that miR-185-5p may exert an essential clinical implication in childhood asthma patients. However, relevant evidence is scarce.…”

Advances and Highlights of miRNAs in Asthma: Biomarkers for Diagnosis and Treatment

“…Other research described a novel regulatory pathway involving miR-19a, which is critical to the severe asthma phenotype, in which down-regulation of miR-19a expression could be explored as a potential new therapy to modulate epithelial repair in asthma by targeting the TGFβR2 gene [ 51 ]. We recently reported that miR-185-5p, a miRNA previously associated with asthma disease in serum, was able to control the synthesis of the matricellular protein periostin in airway structural cells, and could modulate the contraction of bronchial smooth muscle cells through the regulation of RhoA and CDC42, thereby making it a promising therapeutic target [ 52 ].…”