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Published on: September 17, 2021
miR-144 targets in myocardial hypertrophy and coronary microvascular dysfunction in hypertrophic cardiomyopathy:
Maria Lombardi1, Monica Barki2, Lucia Spartano1
1Cardiovascular Research Center, IRCCS San Raffaele Hospital, Via Olgettina, 60, 20132, Milan, Italy.
Insights
MicroRNA-144-3p (miR-144) is downregulated in hypertrophic cardiomyopathy (HCM), impacting cardiac remodeling and coronary microvascular dysfunction (CMD). Its dysregulation suggests a dual role in HCM pathogenesis.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) involves left ventricular hypertrophy, diastolic dysfunction, and coronary microvascular dysfunction (CMD).
- MicroRNA-144-3p (miR-144) is implicated in HCM pathophysiology.
- This study explores miR-144's role in HCM, focusing on cardiac remodeling and CMD.
Purpose of the Study:
- Investigate the relationship between miR-144, its target genes, and phenotypic features of cardiac remodeling and CMD in obstructive HCM.
- Analyze miR-144 expression in cardiomyocytes and arterioles.
- Assess the correlation between miR-144 levels and clinical parameters.
Main Methods:
- Integrated molecular data (RT-qPCR, ELISA, Western blot) with echocardiography (ECHO) and cardiac magnetic resonance (CMR).
- Laser capture microdissection to isolate cardiomyocyte and arteriole areas for miR-144 analysis.
- Quantified expression of miR-144 and its target genes (EZH2, mTOR, VEGF-A, etc.).
Main Results:
- Downregulated miR-144 in HCM myocardium correlated with restrictive physiology and negative atrial remodeling.
- Upregulated miR-144 target genes (mTOR, EZH2) in arterioles linked to hypertrophy and diastolic dysfunction.
- Evidence of inefficient translation and impaired myocardial relaxation, suggesting CMD.
Conclusions:
- miR-144 may act as a molecular regulator in HCM.
- Findings suggest a dual role for miR-144 in both cardiac hypertrophy and CMD.
- miR-144 dysregulation contributes to HCM pathophysiology.
Aims:
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and coronary microvascular dysfunction (CMD). The microRNA-144-3p (miR-144) has recently emerged as a player in HCM. This study investigates the relationship between phenotypic features of cardiac remodelling and CMD in patients with obstructive HCM and either myocardial miR-144 or target genes associated with hypertrophy and angiogenesis, namely EZH2, mTOR, VEGF-A, FGF2, CNPY-2, HIF-1α, ARNT and TP53.
Methods And Results:
Molecular data obtained by RT-qPCR, ELISA, and Western blot were integrated with echocardiographic (ECHO) and cardiac magnetic resonance (CMR) parameters of HCM patients. The miR-144 was also analysed in cardiomyocyte and arteriole areas isolated by laser capturing. The expression level of miR-144 was downregulated in HCM vs. control myocardium and correlated with CMR parameters, suggesting restrictive physiology. The miR-144 expressed by wall thickened arterioles was dramatically reduced in comparison with the cardiomyocyte areas and was correlated with negative atrial remodelling. Upregulation of miR-144 target genes including mTOR and EZH2 was observed, was prevalent in arteriole areas, consistent with hypertrophy triggering protein synthesis, and correlated with markers of diastolic dysfunction and structural remodelling by ECHO. Although VEGF-A/HIF-1α pathway genes and VEGF-A protein were upregulated, the HIF-1α and CNPY2 proteins were not. These findings suggest inefficient translation, supportive of CMD, of impaired myocardial relaxation and left atria enlargement.
Conclusions:
These data suggest the potential role of miR-144 as molecular regulator in HCM, supporting a dual role in hypertrophy and CMD.
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