1School of Pharmacy, Fudan University, Shanghai 201203, China
2School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
Background(#br)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 a significant endogenous gasotransmitter, hydrogen sulfide has been reported to play vital roles on cardiovascular system. S-Propargyl-cysteine (SPRC), a novel endogenous hydrogen sulfide donor, is proved to mediate the formation of hydrogen sulfide to inhibit myocardial apoptosis and reduce oxidative stress to protect against acute myocardial ischemia. In order to produce more stable and sustaining hydrogen sulfide, we modified the dosage form to get SPRC controlled release formulation (SPRC (RS)). In this work, we elucidated the possible cardioprotective effects of this formulation on HF rats and investigated... the involved mechanisms on apoptosis and oxidation.(#br)Methods(#br)Left coronary artery was occluded to induce HF model of rat. The survival rats were then divided into 7 groups (Sham, Model, SPRC, SPRC (RS), SPRC (RS)+PAG, PAG and Digoxin) after 24h and treated with drugs for 6weeks. Echocardiographic indexes including LV, LVID, LVPW, LVAW, EF and FS were recorded to determine the cardiac function. TTC staining was performed to determine the infarct size. Plasmatic level of hydrogen sulfide was detected by modified sulfide electrode. The enzymatic activities of SOD, CK, CAT and GSH were determined by colorimetry. The proteins extracted from myocardial tissues were determined by Western blot.(#br)Results(#br)The cardioprotective effects of SPRC (RS) on HF rats were confirmed by significant reduction of infarct size and improvement of cardiac function, with better effects than normal SPRC. LVAW, LVPW, FS and EF were elevated in SPRC (RS)-treated group compared with model group, while LV and LVID decreased. SPRC (RS) modulated antioxidant defenses in HF rats by preserving plasmatic levels of GSH, CAT and SOD and reducing CK leakage from cells. In addition, SPRC (RS) was shown to increase protein expression of Bcl-2 and decrease protein expression of Bax, caspase-3 and caspase-9 in infarct area to protect against myocardial apoptosis. Furthermore, SPRC (RS) promoted protein expression of CSE, then elevated plasmatic concentration of hydrogen sulfide. These effects of SPRC (RS) could be abolished by PAG, an inhibitor of CSE.(#br)Conclusion(#br)All experiment data indicated the SPRC controlled release formulation played a cardioprotective role on chronic heart failure after myocardial infarction, which was confirmed by improved cardiac function, decreased myocardial apoptosis and preserved oxidative stress. Endogenous hydrogen sulfide was partly involved in these protective effects of SPRC (RS). More important, SPRC (RS) exerted better effects than normal SPRC from all sides, that providing a new perspective on hydrogen sulfide-mediated drug therapy.