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Recent evidence has shown that Mitogen-activated protein kinases (MAPKs) and Rho-associated coiled-coil containing protein kinase 1 (ROCK 1) participate in cardiac fibrosis progression following myocardial infarction (MI). In previous studies we have characterized a novel cardioprotective molecule designated ZYZ-168. ZYZ-168 has been revealed to have anti-apoptotic effects in cardiomyocytes in vitro and to reduce MI damage in vivo. Therefore, the current study was designed to evaluate the therapeutic potential of ZYZ-168 towards cardiac fibrosis following MI induction.
ZYZ-168 was administered to rats subjected to coronary artery ligation over a period of six weeks. Two weeks and six weeks after MI, cardiac function was determined using echocardiography along with protein expression and histological analyses. In addition, the effects of ZYZ-168 on the fibrotic responses of cultured cardiac fibroblast exposed to transforming growth factor-β (TGF-β) were also studied.
Treatment with ZYZ-168 significantly improved cardiac function in animals and reduced interstitial fibrosis following MI induction. The expression of α-smooth muscle actin (α-SMA), and Collagen I were significantly reduced as was the activity of matrix metalloproteinase 9 (MMP-9). In cultured cardiac fibroblasts stimulated with TGF-β, ZYZ-168 appeared to inhibit the fibrotic responses in a concentration dependent manner. Importantly, ZYZ-168 was found to suppress TGF-β-induced ROCK1 activation via inhibition of the phosphorylation status of extracellular signal-regulated kinase (ERK).
ZYZ-168 inhibits cardiac fibrosis induced by MI and TGF-β-induced myofibroblasts differentiation, via the inhibition of the ERK-ROCK1 pathway. ZYZ-168 may be a potential drug candidate for myocardial fibrosis.