87 MiR-24 was found to be correlated with ECM remodeling and TGFβ, in a mouse model of MI. In particular, miR-24
was reported downregulated in the infarct zone after MI, and miR-24 treatment flt-3 led to fibrosis attenuation and improved cardiac function. In vitro experiments conducted in CFs showed that miR-24 upregulation could specifically decrease the differentiation and migration of CFs, and reduce fibrosis. 82 The same team also demonstrated that miR-24 may act via suppressing its target furin, which is essential for TGF-β secretion, whose secretion is reduced upon miR-24 overexpression in CFs. 82 In conclusion, miR-24 downregulation in response to MI possibly serves to promote cardiac fibrosis after MI, which has been identified as a contributive factor to the development of HF. MiR-133a is observed deregulated in HF and may have a role in ECM remodeling during HF. In specific, miR-133a and miR-30 has been found downregulated in the homozygous Ren2 rat model of hypertension-induced HF, and in rats having undergone TAC. The
downregulation of these miRNAs in pathological LVH paralleled the increased expression of the profibrotic protein CTGF. 88 In vitro experiments in CMCs and CFs showed that both miRNAs target CTGF, the expression of which was associated with increased collagen synthesis. 88 Moreover,
a recent study in the DBL transgenic mouse model of HCM (described earlier in this review) reported the downregulation of mir-1 and -133 before ECM remodeling and mir-1,-133 and -30 in end-stage HCM, overall suggesting a distinct role for these miRNAs in pathological ECM remodeling throughout the course of LVH development in HF. 75 In addition to the pool of residing interstitial CFs, recent studies suggest that epicardial mesothelial cells (EMCs) lining the heart and microvascular endothelial cells may also contribute to the injury-induced fibrotic process in the myocardium. In adults, EMCs can undergo epithelial-to-mesenchymal transition Cilengitide (EMT) due to reactivation of the developmental program or during cardiac injury (e.g. MI). 114–118 Several research groups have provided in vitro and in vivo 115-117 evidence that EMT of EMCs occurring in the injured adult myocardium can give rise to fibroblast-like cells, which contribute to the default repair-driven fibrotic response. Interestingly, Bronnum and partners showed in 2013 that miRNAs are capable of regulating fibrogenic EMT of the EMCs in the adult heart. 119,120 In specific, they found that pro-fibrotic TGF-beta treatment promoted EMT progression in EMC cultures, resulting in expression changes of numerous miRs, and especially miR-21.