Abstract 16834: Cardiac and Circulating Levels of MicroRNA-21 Reflect Myocardial Fibrosis in Aortic Stenosis Patients
Background: Aberrant expression of microRNAs (miRNA) has been recently associated with various cardiovascular pathophysiological conditions and circulating miRNAs are emerging as promising biomarkers. MiR-21 overexpression has been related to cardiac fibrotic responses to biomechanical stress. The aim of this study was to investigate the clinical value of miR-21, cardiac and plasmatic, as biomarker for pathological myocardial fibrosis progression secondary to pressure overload.
Methods: In LV biopsies from 17 controls and 39 patients with aortic stenosis (AS), we quantified the expression levels of miR-21 normalized to U6B (qRT-PCR) and determined their relationship with mean transvalvular gradients (continuous wave Doppler) and with myocardial expression of remodeling-related genes (qRT-PCR). Total RNA was isolated from plasma using TRIzol. Spiked-in C. elegans-miR-39 was used as control. Reverse transcription was performed using miR-21 and cel-miR-39 specific primers. qRT-PCR was performed with Taqman assays. miR-21 levels were normalized to cel-miR-39.
Results: Myocardial expression levels of miR-21 were significantly higher in AS patients compared with controls (Control: 115±14 vs AS: 189±26; p<0.05) and correlated directly with the mean transvalvular gradient (R=0.51**). A direct relationship between the myocardial expression levels of miR-21 and the mRNA levels of TGF-β1 (R=0.42, p<0.05), its effectors [SMAD4 (R= 0.44; p<0.05) and TAK1 (R=0.41, p<0.05)] and fibrosis-related target genes [collagen I (R=0.47; p<0.01), collagen III (R=0.58; p<0.001) and fibronectin (R=0.61; p<0.05)] was also observed. Plasma levels of miR-21 were up-regulated in AS patients (Control: 15.0±7.5 vs AS: 182.4±97.8; p<0.05) and correlated directly with the myocardial expressions of SMAD4 (R= 0.57; p<0.01), TAK1 (R=0.51, p<0.01), collagen I (R=0.50; p<0.01) and fibronectin (R=0.41; p<0.05).
Conclusions: These results support the emerging role of miR-21 as a regulator of the fibrotic process developed in response to pressure overload in AS patients. Our data underscore the value of circulating miR-21 as biomarker of fibrosis with potential prognostic value.
- © 2011 by American Heart Association, Inc.