Research Article: Integrated analysis of MYH6, MYH7, and MYH7B expression and their associated microRNAs in human end-stage heart failure
Abstract:
Cardiac contractility is regulated by two myosin heavy chain (MHC) protein isoforms, ? and ?, encoded by the MYH6 and MYH7 genes. The intronic regions of these genes encode the microRNAs miR-208a and miR-208b , which are key regulators of cardiac hypertrophy. Functionally relevant long non-coding RNAs (lncRNAs) have also been identified at these loci, such as those transcribed in the antisense direction from the MYH7 gene, including the primary miR-208b transcript ( MHRT ) originating from an internal MYH7 promoter. Additionally, MYH7B , another cardiac sarcomeric myosin gene, serves as a precursor for miR-499a-5p .
This study aimed to comprehensively analyse the expression profiles of MYH6, MYH7, and MYH7B genes, microRNAs ( miR-208a-3p, miR-208b-3p, and miR-499a-5p ), and the lncRNA MHRT in non-failing and end-stage failing human left ventricles.
The relative expression of these transcripts was measured using RT-qPCR in left ventricular samples from 5 non-failing controls and 24 patients with end-stage heart failure, including hypertrophic cardiomyopathy (HCM, n =?4), dilated cardiomyopathy (DCM, n =?10), and coronary artery disease (CAD, n =?10). The findings were validated by comparison with two independent RNA-seq datasets (GSE141910 and GSE116250) for MYH6 , MYH7 , MYH7B , and MHRT .
Statistical analysis of independent RNA-seq datasets confirmed strong correlations among MYH7, MYH7B, and MHRT transcripts ( p ??0.0001), a trend also observed in our RT-qPCR cohort. A profound imbalance in the MYH7B/miR-499-5p ratio was identified, shifting from ?250:1 in non-failing controls to ?12–18:1 in failing hearts. The miR-208a-3p/miR-208b-3p expression ratio was heavily skewed toward miR-208b-3p (?50:1) in all groups, regardless of disease status.
Our results suggest that MYH7, MYH7B , and MHRT transcripts exhibit coordinated expression patterns in human left ventricles, independent of pathological status. We further observed a dissociation between miR-208a-3p and its host gene ( MYH6 ) under physiological conditions and confirmed altered miR-499a-5p/MYH7B relationships, consistent with findings in murine models. Moreover, the expression of two regulatory genes, SOX6 and TARBP2 , known to modulate MYH7 and MYH7B in mice, showed that SOX6 is upregulated in the left ventricles of all pathological groups.
Introduction:
Cardiac contractility is regulated by two myosin heavy chain (MHC) protein isoforms, ? and ?, encoded by the MYH6 and MYH7 genes. The intronic regions of these genes encode the microRNAs miR-208a and miR-208b , which are key regulators of cardiac hypertrophy. Functionally relevant long non-coding RNAs (lncRNAs) have also been identified at these loci, such as those transcribed in the antisense direction from the MYH7 gene, including the primary miR-208b transcript ( MHRT ) originating from an internal MYH7…
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