94 In specific, miR-1 and miR-133a have been found to be downregulated

in mouse and rat models of hypertrophy, but PA-824 concentration upregulated in canine hearts isolated from animals with chronic HF. 94 Moreover, in the chronic HF animals, miR-1 and miR-133 were shown to be implicated in the development of arrhythmogenesis, 94 a characteristic observed in approximately 50% of congestive HF cases. 95,96 These findings indicate that miR-1 and miR-133 serve distinct stage-specific roles during the course of HF. Their precise mode of action is discussed in subsequent sections. The time course of HCM-HF progression has also been explored in the DBL transgenic mouse model of HCM, which bears mutations in troponin I and myosin heavy chain genes (TnI-203/MHC-403) and presents with severe HCM, HF, and premature death. 75,97 Measurements in 335 miRNAs showed downregulation of miR-1 and miR-133 in a pre-disease state, and this change preceded upregulation

of target genes causal of cardiac hypertrophy and ECM remodeling, thus implying a role in early disease development, consistently with other studies. 71–76 In end-stage HCM the miRNA signature comprised of 16 miRNAs and corresponded to those of cardiac stress and hypertrophy, including downregulation of miR-1, -133, -30 and -150, and overexpression of miR-21, -199 and -214. This group also engaged microarrays to detect differentially expressed mRNAs in end-stage HCM, and bioinformatical analysis to predict mRNA-miRNA interactions amongst the significantly changed transcripts and miRNAs. As a result, some of the altered miRNAs (miR-1, -21, -30, -31, -133, -150, -222, -486) were further associated with hypertrophy, CMC proliferation, cardiac electrophysiology, calcium signaling, fibrosis, and the TGF-β pathway, based on their predicted interaction with the dysregulated transcripts and the Gene Ontology annotations of the latter. 75 These findings suggest that miRNAs play a critical role in the cardiac pathophysiology of the DBL mouse model during end-stage HCM. In search of the distinct miRNAs implicated in different stages of hypertrophy-induced HF, miRNA expression alterations have

also been investigated during the transition from right ventricular hypertrophy (RVH) to HF in mice that underwent pulmonary artery constriction (PAC). 100 In Brefeldin_A addition to left ventricular pathological remodeling, which accompanies the majority of failing hearts, RVH may also lead to failure, predominantly in cases with congenital right-sided cardiac defects. Reddy et al used microarrays to measure the expression of 567 miRNAs in the right ventricle of mice at 2, 4, 10 days post-PAC or sham operation, time points which correspond to early compensated hypertrophy, early decompensated hypertrophy and overt HF, respectively. Although no significant changes were detected at 2 days, at 4 and 10 days, 32 and 49 miRNAs, respectively, were deregulated.