The miR-195 transgenic animals developed

pathological cardiac hypertrophy and HF, thus revealing a direct and sufficient role of miR-195 in the development of HF in mice. Mir-24 transgenic mice died at the embryonic stage, whilst overexpression of mir-214 had no phenotypic effect. Similarly, Ucar CYP450 inhibitor et al investigated the role of miR-212 and -132, also upregulated during hypertrophy in the heart of TAC mice. 103 Transgenic mice with cardiac specific overexpression of miR-212 and -132 presented with hypertrophic hearts, exhibited signs of severe HF and experienced premature death. In vitro experiments from the same group showed that miR-212 and -132 target the anti-hypertrophic TF Foxo3a, whilst overexpression of miR-212 and -132 results in hyperactivation of pro-hypertrophic calcineurin/NFAT signaling. 103 MiR-23a levels have also been found elevated in rodent models of hypertrophy,

and specifically upon isoproterenol-induced cardiac hypertrophy in mice, 80 as well as pressure overload-induced hypertrophy in both mice and rats. 93 In order to elucidate its role, Wang et al produced transgenic mice with cardiac overexpression of miR-23a, which presented with exaggerated hypertrophy upon phenylephrine (PE) treatment or pressure overload induced by TAC. 81 This study also reported that endogenous miR-23a was upregulated by hypertrophic stimuli (PE, endothelin, ET) in cultured CMCs, thereby indicating that miR-23a participates in the transduction of the hypertrophic signal. Moreover, they identified the anti-hypertrophic Foxo3a as a target of miR-23a, and showed that miR-23a and Foxo3a bi-transgenic mice present with an attenuated hypertrophic response, in comparison to the miR-23a transgenic mice alone. 81 Interestingly, in vitro studies by other teams revealed additional molecular players in the putative miR-23a pro-hypertrophic machinery. Specifically, experiments in CMCs showed that the nuclear

factor of activated T cells 3 (NFATc3) induces miR-23a, which in turn targets the negative regulator of hypertrophy muscle ring finger1 (MuRF1) Batimastat thereby triggering cardiac hypertrophy (Figure 2). 80,104 Figure 2. The role of miR-132, -212 and -23a in molecular pathways of cardiac hypertrophy. Activation of calcineurin/NFAT pro-hypertrophic pathway leads to increased expression of miR-23a. MiR-23a targets the negative regulator of hypertrophy muscle ring finger1 … Mir-27b has been seen upregulated in cardiac hypertrophy, and specifically in the cardiac-specific Smad4 knockout mouse model. 105 Importantly, cardiac-specific overexpression of miR-27b in transgenic mice was sufficient to induce hypertrophy and heart dysfunction, 105 thereby implying a direct association.