microRNA-122 down-regulation may play a role in severe myocardial fibrosis in human aortic stenosis through TGF-β1 up-regulation

Abstract

miRNAs (microRNAs) have been shown to play a role in myocardial fibrosis. The present study was designed to analyse whether alterations in miRNA expression contribute to the progression of myocardial fibrosis in AS (aortic valve stenosis) patients through up-regulation of the pro-fibrotic factor TGF-β1 (transforming growth factor-β type 1). Endomyocardial biopsies were obtained from 28 patients with severe AS, and from the necropsies of 10 control subjects. AS patients presented increased myocardial CVF (collagen volume fraction) and TGF-β1 compared with the controls, these parameters being correlated in all patients. Patients were divided into two groups by cluster analysis according to their CVF: SF (severe fibrosis; CVF >15%; n=15) and non-SF (CVF ≤15%; n=13). TGF-β1 was increased in patients with SF compared with those with non-SF. To analyse the involvement of miRNAs in SF, the miRNA expression profile of 10 patients (four with non-SF and six with SF) was analysed showing that 99 miRNAs were down-regulated and 19 up-regulated in the SF patients compared with the non-SF patients. Those miRNAs potentially targeting TGF-β1 were validated by real-time RT (reverse transcription)-PCR in the whole test population, corroborating that miR-122 and miR-18b were down-regulated in patients with SF compared with those with non-SF and the control subjects. Additionally, miR-122 was inversely correlated with the CVF, TGF-β1 and the TGF-β1-regulated PCPE-1 (procollagen C-terminal proteinase enhancer-1) in all patients. Experiments in human fibroblasts demonstrated that miR-122 targets and inhibits TGF-β1. In conclusion, for the first time we show that myocardial down-regulation of miR-122 might be involved in myocardial fibrosis in AS patients, probably through TGF-β1 up-regulation.

The NTR domain of procollagen C-proteinase enhancer-1 (PCPE-1) mediates PCPE-1 binding to syndecans-1, -2 and -4 as well as fibronectin

“…Kessler et al, 1990) and its expression increases in fibrosis in parallel to the characteristic increase in collagen expression (Ogata et al, 1997;Shalitin et al, 2003;Kessler-Icekson et al, 2006;Yu et al, 2013;Beaumont et al, 2014). Thus, PCPE-1 seems to function as a specific positive regulator of collagen deposition.…”

BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling

“…Also, since PCPE-2 is relatively highly expressed in heart, cardiac fibrosis induced in Pcolce2 −/− mice by transverse aortic constriction was studied and found to result in lower collagen deposition, compared to wild-type, with reduced myocardial stiffness and increased survival [96]. Finally, the first study of PCPE-1 expression conducted on human samples showed a significant increase of protein levels in myocardial fibrosis linked to aortic valve stenosis [97]. These latter results support the potential of PCPEs as new targets for anti-fibrotic therapies.…”

Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5

“…Left ventricular (LV) pressure overload, as seen in patients with aortic stenosis, increases transforming growth factor beta (TGF-β) signaling [1]. This, in turn, activates cardiac fibroblasts (CFB) and leads to myocardial fibrosis due to increased CFB production of extracellular matrix (ECM) i.e.…”