ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation

Selective treatments for myocardial infarction (MI) induced cardiac fibrosis are lacking. In this study,\r\nwe focus on the therapeutic potential of a synthetic cardio-protective agent named ZYZ-168 towards\r\nMI-induced cardiac fibrosis and try to reveal the underlying mechanism. ZYZ-168 was administered\r\nto rats with coronary artery ligation over a period of six weeks. Ecocardiography and Masson staining\r\nshowed that ZYZ-168 substantially improved cardiac function and reduced interstitial fibrosis. The\r\nexpression of α–smooth muscle actin (α-SMA) and Collagen I were reduced as was the activity of\r\nmatrix metalloproteinase 9 (MMP-9). These were related with decreased phosphorylation of ERK1/2\r\nand expression of Rho-associated coiled-coil containing protein kinase 1 (ROCK1). In cardiac fibroblasts\r\nstimulated with TGF-β1, phenotypic switches of cardiac fibroblasts to myofibroblasts were observed.\r\nInhibition of ERK1/2 phosphorylation or knockdown of ROCK1 expectedly reduced TGF-β1 induced\r\nfibrotic responses. ZYZ-168 appeared to inhibit the fibrotic responses in a concentration dependent\r\nmanner, in part via a decrease in ROCK 1 expression through inhibition of the phosphorylation status\r\nof ERK1/2. For inhibition of ERK1/2 phosphorylation with a specific inhibitor reduced the activation of\r\nROCK1. Considering its anti-apoptosis activity in MI, ZYZ-168 may be a potential drug candidate for\r\ntreatment of MI-induced cardiac fibrosis.