Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients

Abstract

Background: Various human cardiovascular pathophysiological conditions associate aberrant expression of microRNAs (miRNAs) and circulating miRNAs are emerging as promising biomarkers. In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. This study was designed to determine the role of myocardial and plasmatic miR-21 in the maladaptive remodeling of the extracellular matrix induced by pressure overload in aortic stenosis (AS) patients and the clinical value of miR-21 as a biomarker for pathological myocardial fibrosis.

Methods: In left ventricular biopsies from 75 AS patients and 32 surgical controls, we quantified the myocardial transcript levels of miR-21, miR-21-targets and ECM- and TGF-β-signaling-related elements. miR-21 plasma levels were determined in 25 healthy volunteers and in AS patients. In situ hybridization of miR-21 was performed in myocardial sections.

Results: The myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with the controls and correlated directly with the echocardiographic mean transvalvular gradients. miR-21 overexpression was confined to interstitial cells and absent in cardiomyocytes. Using bootstrap validated multiple linear regression, the variance in myocardial collagen expression was predicted by myocardial miR-21 (70% of collagen variance) or plasma miR-21 (52% of collagen variance), together with the miR-21 targets RECK and PDCD4, and effectors of TGF-ß signaling.

Conclusions: Our results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis.

Keywords: AS; Aortic stenosis; Col; ECM; FN; LV; MicroRNA; Myocardial fibrosis; PDCD4; PTEN; Plasma miR-21; RECK; SPRY1; TAK-1; TGF-ß signaling; TGF-β; TGF-β activated kinase-1; TIMP3; aortic stenosis; collagen; extracellular matrix; fibronectin 1; left ventricle; miRNA; microRNA; phosphatase and tensin homolog; programmed cell death 4; reversion-inducing-cysteine-rich protein with kazal motifs; sprouty homolog 1; tissue inhibitor of metalloproteinase 3; transforming growth factor-β.