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Myosins and MyomiR Network in Patients with Obstructive Hypertrophic Cardiomyopathy

Chiara Foglieni1, Maria Lombardi1, Davide Lazzeroni1

  • 1Cardiovascular Research Center, IRCCS San Raffaele Hospital, 58, 20132 Milan, Italy.

Biomedicines
|September 23, 2022
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) involves myosin protein and gene expression changes, with the MyomiR network potentially modulating disease phenotypes and offering new therapeutic targets.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Genetic Diseases

Background:

  • Hypertrophic cardiomyopathy (HCM) is a primary genetic heart muscle disorder.
  • The molecular underpinnings of HCM's diverse clinical presentations remain unclear.
  • Understanding gene and protein regulation in HCM is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the relationship between clinical phenotype, cardiac myosin expression, and the MyomiR network in HCM.
  • To identify molecular mechanisms contributing to HCM pathophysiology.
  • To explore potential therapeutic targets within the myosin/MyomiR axis.

Main Methods:

  • Analysis of myocardial biopsies from HCM patients and controls using mass spectrometry and RNA sequencing.
  • Laser-capture microdissection to isolate cardiomyocytes for gene expression analysis.
  • In vitro studies using induced pluripotent stem cell-derived cardiomyocytes to model MyomiR-gene interactions.

Main Results:

  • Reduced cardiac myosin heavy chain 6 (MyHC6) protein in HCM compared to controls.
  • Elevated MYH7, MYH7B, and MYLC2 gene expression in HCM, with comparable MYH6 levels.
  • Upregulation of Mhrt and specific miR-499 target genes (SOX6, PTBP3) in HCM, with mutations correlating to PTBP3 and SOX6.
  • In vitro studies showed a time-dependent link between MyomiRs and myosin genes, mimicking HCM findings.

Conclusions:

  • HCM exhibits an uncoupling between myosin protein and gene expression.
  • The myosin/MyomiR network plays a modulatory role in HCM myocardium.
  • These findings suggest potential therapeutic strategies targeting the MyomiR network for HCM treatment.

Keywords:
MyomiR (myosin-encoded miRs)Polypyrimidine Tract Binding Protein 3 (PTBP3)SRY-Box Transcription Factor 6 (SOX6)cardiomyocyteshypertrophic cardiomyopathy (HCM)miR-499microRNA (miRs)myosin heavy chain (isoform: MyHC, gene: MYH)

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