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

Objective: Heart failure (HF) is one of the most serious diseases worldwide. S-propargyl-cysteine (SPRC), a novel modulator of endogenous hydrogen sulfide, is proved to be able to protect against acute myocardial ischemia. In order to produce more stable and sustainable hydrogen sulfide, we used controlled release formulation of SPRC (CR-SPRC) to elucidate possible cardioprotective effects on HF rats and investigate involved mechanisms on apoptosis and oxidation., Methods: Left coronary artery was occluded to induce HF model of rat. The survival rats were randomly divided into 7 groups after 24 hours and treated with drugs for 6 weeks. Echocardiographic indexes were recorded to determine cardiac function. TTC staining was performed to determine infarct size. Plasmatic level of hydrogen sulfide was detected by modified sulfide electrode. Activity of enzyme and expression of protein were determined by colorimetry and Western blot, respectively., Results: The cardioprotective effects of CR-SPRC on HF rats were confirmed by significant reduction of infarct size and improvement of cardiac function, with better effects compared to normal SPRC. CR-SPRC modulated antioxidant defenses by preserving levels of GSH, CAT and SOD and reducing CK leakage. In addition, CR-SPRC elevated ratio of Bcl-2/Bax and inhibited activity of caspases to protect against myocardial apoptosis. The cardioprotective effects of CR-SPRC were mediated by hydrogen sulfide., Conclusions: All experiment data indicated cardioprotective effects of CR-SPRC on HF rats. More importantly, CR-SPRC exerted better effects than normal SPRC in all respects, providing a new perspective on hydrogen sulfide-mediated drug therapy.

3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (ZYZ451) was found to be an excellent cardio-protective agent in the previous research in our lab. However, its potent therapeutic effects on myocardial infarction and the underlying mechanism remain elusive. In the present study, we demonstrate that ZYZ451 protects neonatal rat ventricular cardiomyocytes (NRVCs) from hypoxia-induced apoptosis via increasing manganese-containing superoxide dismutase (MnSOD) activity and inhibiting mitochondrial reactive oxidative species (mitoROS) production. MnSOD knockdown impairs the anti-apoptotic effects of ZYZ451. We report here for the first time that signal transducer and activator of transcription 3 (STAT3), an important nuclear transcriptional factor also identified in mitochondria, co-localizes with MnSOD and interacts with it, as determined by using methods of co-immunofluorescence and co-immunoprecipitation. Knockdown of STAT3 rather than inhibition of STAT3 phosphorylation results in a significant reduction in MnSOD activity. Furthermore, interaction between MnSOD and STAT3 is diminished in STAT3 deficient H 9 C 2 cells. Its novel subcellular localization and interaction with MnSOD suggest that STAT3 may be involved in regulation of MnSOD activity beyond its transcriptional potential. Consistent with the results in vitro, ZYZ451 reduces myocardial infarct size as well as cardiomyocytes apoptosis, inhibits lactate dehydrogenase (LDH) and malondialchehyche (MDA) release, and restores MnSOD activity in peri-infarct hearts. These benefits appear to be attributed to the enhanced interaction between STAT3 and MnSOD. These findings shed a light on a new role of STAT3 in oxidative stress and suggest that ZYZ451 is likely an effective cardio-protective agent. [ABSTRACT FROM AUTHOR]

SCM-198 (Leonurine) has attracted great attention due to its cardioprotective effects in myocardial infarction (MI). However, no systematic modifications and structure-activity relationship (SAR) studies could be traced so far. In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H 2 O 2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μ M and 10 μ M concentrations. LDH release level in cells treated with 1 μ M 14o was comparable with cells treated with 10 μ M SCM-198. Results of Bcl-2 expression and caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with 14o had much lower infarct size compared with that of SCM-198. The mechanism study suggested that 14o improved cardiac morphology and reduced apoptosis of cardiomyocytes in the border zone of infarction, as proved by H&E and TUNEL staining. Image 1 • 35 Analogs of SCM-198 were designed, synthesized and biologically evaluated. • Analog 14o significantly reduced cardiomyocytes apoptosis. • The mice pretreated with 14o had much lower infarct size than that of SCM-198. • 14o might be a potential cardioprotective agent to treat acute myocardial infarction. [ABSTRACT FROM AUTHOR]