105 Overall, miR-195, -212, -132, -27b emerge as potent inducers of cardiac hypertrophy, while miR-23a appears to serve Bcl-2 lymphoma as a contributive factor to the establishment of this pathology. In addition to upregulated pro-hypertrophic miRNAs, disruption of anti-hypertrophic miRNAs expression has also been reported in the hypertrophied and failing myocardium. A representative example is miR-1, which was downregulated

in a series of studies in rodent models of hypertrophy, HCM and HF (TAC, AKT overexpression, MHCα-CN mice, cardiac specific Dicer deletion, and DBL transgenic mice). Ikeda et al demonstrated that the size of miR-1 deficient neonatal rat CMCs was significantly increased at baseline and after treatment with pro-hypetrophic stimulus (ET), indicating that miR-1 downregulation promotes hypertrophic growth. According to further studies in CMCs, miR-1 inhibits cell growth-related targets (RasGAP, Cdk9, fibronectin, Rheb), reduces protein synthesis and cell size, and its downregulation promotes hypertrophy. 74 In addition, in vitro experiments in a series of studies revealed multiple putative mechanisms of action for mir-1-mediated hypertrophy suppression, 76,71–75 including targeting of Igf-1 and Igf1-r,

71 calmodulin, Mef2a and Gata4. 72 These data indicate that miR-1 targets key regulators of hypertrophic growth, and may thus act as a central suppressor of hypertrophy via a range of downstream effectors in the failing myocardium. Similarly, the newly described miR-378 has been shown to be down-regulated during hypertrophic growth and HF. Studies in rat CMCs have shown that deficiency of this

miRNA is sufficient to induce fetal gene expression, thereby suggesting an anti-hypertrophic role in HF. MiR-378 seemingly acts by negatively regulating the MAPKs pathway. In specific, multiple components of this pathway have been identified as miR-378 targets (Mapk1, Igfr1, Grb2, Ksr1) by Ganesan et al. 108 In addition, recent experiments in rat CMCs showed that miR-378 directly targets Cilengitide Grb2 and blocks Ras activation, resulting in negative regulation of fetal gene expression and cardiac hypertrophy. 106,107 MiR-9 is also downregulated following hypertrophic treatments, and confers anti-hypertrophic effects in the murine heart. Wang et al utilized the isoproterenol and aldosterone-induced mouse models of hypertrophy to demonstrate that NFATc3 can promote hypertrophy via induction of myocardin expression, while miR-9 targets and suppresses myocardin. 109 Whether miR-9 is also underexpressed in human HF and may thus provide a target towards pathological hypertrophy HF inhibition, is yet to be determined. miRNAs impact on ECM remodeling and fibrosis Besides the establishment of hypertrophy and/or dilatation, the failing myocardium is often accompanied by structural remodeling.