miR-144 targets in myocardial hypertrophy and coronary microvascular dysfunction in hypertrophic cardiomyopathy: molecular research meets imaging

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.