s-propargylcysteine and Myocardial-Infarction

We previously reported that S-propargyl-cysteine (SPRC) exerts cardioprotective effects by elevating H2S levels via the CSE/H2S pathway. In the present study, we investigated the cardioprotective effects and pharmacokinetic properties of a controlled release formulation of SPRC (CR-SPRC) in an in vivo rat model of myocardial infarction (MI). Rats were randomly assigned to seven groups that were pre-treated with CR-SPRC daily for 7 days prior to ligation of the left anterior descending coronary artery to induce MI. Cardiac function and infarct size were determined after MI, and we examined the activity of antioxidant enzymes, expression of anti-inflammation proteins and hydrogen sulfide levels. Mixed-mode, reversed-phase and cation-exchange HPLC-MS/MS were used to compare the pharmacokinetic properties of CR-SPRC and SPRC. CR-SPRC significantly reduced infarct size and creatine kinase (CK) and lactate dehydrogenase (LDH) leakage and it preserved cardiac function during MI. CR-SPRC displayed antioxidant properties, preserving glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) levels whereas reducing malondialdehyde (MDA) levels. Moreover, CR-SPRC significantly reduced the protein levels of inflammatory biomarkers (phospho-NF-κB p65/NF-κB p65, TNF-α) and increased cystathionine-γ-lyase (CSE) and Iκ-Bα protein levels. CR-SPRC had better pharmacokinetic properties than SPRC, with a reduced concentration peak (Cmax), prolonged time to reach peak concentration (Tmax), prolonged mean residence time (MRTinf) and increased AUC0-t. CR-SPRC showed protective effects against MI via the CSE/H2S pathway and demonstrated better cardioprotective effects than SPRC by prolonging the release of endogenous H2S.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiotonic Agents; Creatine Kinase; Cysteine; Delayed-Action Preparations; Electrocardiography; Glutathione; Hydrogen Sulfide; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Myocardial Infarction; Rats, Sprague-Dawley; Superoxide Dismutase

In this study, we determined the cardioprotective effects of S-propargyl-cysteine (SPRC), a structural analog of S-allylcysteine (SAC), using in vivo models of acute myocardial infarction (MI) and in vitro hypoxic cardiomyocytes models. MI was created in rats by ligating the left anterior descending coronary artery. Plasma enzymes levels and cystathionine-gamma-lyase (CSE) activities were determined. Primary cultures of newborn rats' cardiomyocytes were injured by hypoxia for 6 h. Cell viabilities were measured with the thiazolyl blue assay. RT-PCR and western blot analysis revealed the expression of CSE in both models. The protective effects of SPRC were associated with an observed reduction in infarct size (20.8 +/- 2.4% vs. 36.0 +/- 1.3%), decreased plasma enzymes levels and reduced malondialdehyde levels when compared to the MI vehicle group (P < 0.05); cardiac function was also improved. SPRC increased CSE activity and plasma H2S concentration by 1.6-fold and 1.3-fold, respectively, in MI rats. Decreased cell viability (64.5 +/- 5.4%) in hypoxic cardiomyocytes could be rescued with use of SPRC (81.0 +/- 3.1%). Similarly, mRNA and protein expression of CSE were upregulated in the SPRC group. Treatment with the CSE inhibitor propargylglycine abolished the protective effects of SPRC. Our study provides novel evidence that SPRC is protective in myocardial infarctions via a H2S-related pathway.

Topics: Animals; Animals, Newborn; Cell Hypoxia; Cell Survival; Cystathionine gamma-Lyase; Cysteine; Disease Models, Animal; Hydrogen Sulfide; Male; Myocardial Infarction; Myocardial Ischemia; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Up-Regulation