c.i, ii), miR-1 and miR-133a were found to be upregulated in canine hearts c-Kit mutation selleck isolated from animals with chronic HF accompanied by increased left ventricular dimensions and impaired contractility of the left ventricle. 94 These miRNAs were shown to target the mRNA of the PP2A catalytic

subunit of RyR2, which led to increased RyR2 phosphorylation and abnormal spontaneous sarcoplasmic reticulum Ca2+ release, thus contributing to arrythmogenesis. 94 These in vivo findings confirm previous studies in rat CMCs, where miR-1 over-expression was shown to decrease the protein phosphatase PP2A regulatory subunit B56alpha, which in turn resulted in increased phosphorylation of the L-type and RyR2 calcium channels, and ultimately enhanced cardiac excitation-contraction. 125 These observations point to miR-1 and miR-133a as regulators of CMC contractility via modulation of calcium signaling, suggesting their implication in arrhythmia manifestation during HF. The role of miR-1 in calcium signaling has been further investigated in additional rodent models of HF. Studies in the cardiomyocyte-specific

SRF knock-out mouse model of HF revealed that sodium-calcium exchanger 1 (NCX1) and AnxA5 mRNAs are targets of miR-1. 126 This is consistent with previous studies in chronic post-myocardial infarction rat model of HF, where miR-1 expression was restored by SERCA2a gene therapy (AAV9.SERCA2a) in the failing heart and led to normalization of NCX1 expression. 127 Of note, miR-1 expression restoration also resulted in improved cardiac function in this model. 127 Moreover, studies in the mouse model of hypertrophy derived from cardiac-specific Dicer deletion, showed that miR-1 also targets sorcin, which functions as a regulator of calcium signaling and excitation-contraction coupling. 76 With regards to the role of SERCA2a in the failing myocardium, functional screening of 875 miRNAs, identified miR-25 as a suppressor of SERCA2a expression and consequently a potent regulator of intracellular calcium handling. MiRNA-25 has also been found overexpressed in human and experimental HF. Moreover, experiments in cardiomyocyte-like

HL-1 cells demonstrated that miR-25 delayed calcium uptake kinetics, whilst Entinostat AAV9-mediated overexpression in a mouse model of HF led to loss of contractile function. Importantly, inhibition of miR-25 expression via antagomiRs in a mouse model of HF halted the established HF, and improved cardiac function and survival, thereby suggesting that miR-25 may be a novel therapeutic target for HF. 180 These findings suggest that miRNAs, among their many mechanisms of contributing to HF, may also impair different aspects of calcium homeostasis in the cardiomyocytes. miRNAs impact on mitochondrial dysfunction underlying HF Interestingly, recent studies suggest that miRNAs may be implicated in HF development via impairing mitochondrial function.