Cardioprotective Effects Of Controlled Release Formulation Of S-Propargyl-Cysteine On Heart Failure Rats And Molecular Mechanisms

Objective:Heart failure (HF) is one of the most serious health issues in both developed and developing countries that causes millions of people suffering. In recent years, as an endogenous gasotransmitter, hydrogen sulfide has been extensively investigated, and is demonstrated to play vital roles on cardiovascular system. S-propargyl-cysteine (SPRC), a novel endogenous hydrogen sulfide donor, can promote the release of hydrogen sulfide to protect against acute myocardial ischemia through inhibiting myocardial apoptosis and reducing oxidative stress. SPRC belongs to BCS I which has high solubility and high permiability, it is transported through film hole and can be well absorbed by oral. The half life of SPRC is short with pungent odor, in order to prolong the action time in vivo, produce more stable and sustainable hydrogen sulfide, reduce irritant at the same time, we modified the dosage form to get SPRC controlled release formulation (CR-SPRC). In this work, we elucidated the possible cardioprotective effects of this formulation on HF rats and investigated the involved mechanisms on apoptosis and oxidation.Methods:We investigated pharmacokinetics of SPRC and CR-SPRC in vitro and in vivo. 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. Angiography was performed to analyze the vascular density in heart. TTC staining and Masson’s staining were used to determine infarct size and myocardial fibrosis. Plasmatic level of hydrogen sulfide was detected by modified sulfide electrode. Enzyme activity and protein expression were determined by colorimetry and Western blot, respectively.Results:CR-SPRC could release slower than SPRC in vitro and in vivo. The cardioprotective effects of CR-SPRC on HF rats were confirmed by significant reduction of infarct size and myocardial fibrosis, as well as improvement of cardiac function and vascular density, with better effects compared with normal SPRC. The cardioprotective effects of CR-SPRC were mediated by hydrogen sulfide. 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 caspases activity to protect against myocardial apoptosis. Furthermore, CR-SPRC reduced the level of ST2, a novel biomarker of cardiac stress, in HF heart.Conclusions:All experiment data demonstrated 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.