88 The differential regulation of those three miRNAs during HF possibly facilitates the extensive ECM remodeling observed in the myocardium (see also 75,87,89 ). Other studies have pinpointed miRNAs related to HF-associated pathologies, such as hypertrophy,
HCM, DCM and ICM. In specific, Foretinib molecular weight studies in left ventricular tissue acquired from HCM patients revealed increased expression of miR-221, which was also upregulated in the hypertrophic (2 weeks) and failing hearts (9 weeks) of TAC mice. Further studies in rat CMCs demonstrated that forced expression of miR-221 by miRNA mimics is capable of inducing hypertrophy and re-expression of fetal genes in vitro, whilst knockdown of endogenous miR-221 abolished these effects. Moreover, in silico target prediction and experimental assays indicated that miR-221 possibly acts via targeting the suppressor of cardiac hypertrophy p27. 90 MiR-499 upregulation in human hypertrophied and failing hearts was associated with decreased expression of an array of predicted targets. Interestingly, studies in mice showed that miR-499 suffices for the induction of HF and acceleration of the pathological remodeling, upon pressure
overload. AKT and MAPKs were amongst the miR-499 numerous targets, while miR-499- induced cardiomyopathy was associated with changes in protein phosphorylation (e.g. HSP90, PP1α), thus revealing a spectrum of putative mechanisms via which miR-499 may contribute to cardiac pathophysiology. 13 Of particular interest is also the upregulation of miR-24 in cardiac tissue of ICM and DCM-related HF, which seemingly accounts for the under-expression of junctophilin 2 (JP2). JP2 is a structural protein that anchors the sarcoplasmic reticulum (SR) to the transverse tubules (TT) of the plasma membrane, which are the major sites of the excitation–contraction coupling. Importantly, transmission electron microscopic imaging revealed a significant reduction in SR-TT junctions in the ICM and
DCM specimens, indicating that miR-24 and JP2 dysregulation may ultimately lead to defective excitation-contraction Cilengitide coupling, a characteristic of failing CMCs. 91 Examples of miRNAs associated with age-related HF include the downregulated miR-18a, -19a and -19b leading to upregulation of the ECM proteins CTGF and TSP1, possibly in the context of ECM remodeling during HF pathogenesis. 77 miRNAs signatures in animal models of HF miRNAs signatures during the development of cardiac pathologies preceding HF: A close up in hypertrophy Besides investigations in human HF, a series of animal model studies, predominantly involving transverse aortic constriction (TAC), have provided valuable insights into the miRNA expression alterations contributing to pathogenesis of hypertrophy and HF.