tanshinone-ii-a-sodium-sulfonate and Myocardial-Ischemia

The activation of NOD-like receptor (NLR) family, pyrin-domain containing 3 (NLRP3) inflammasome has now been proven to have a close connection with myocardial ischemia (MI) during acute phase, but the mechanisms are not completely clear. This study investigated the role of NLRP3 inflammasome in pathogenesis of MI injury including inflammation and lipid accumulation, as well as the effects of sodium tanshinone IIA sulfonate (STS) and diltiazem hydrochloride (DI).. Occlusion of left anterior descending (LAD) in canines was employed to induce MI. STS and DI were given intravenously 15 min after LAD occlusion. Cardiac function, inflammation and lipid levels, as well as related signaling pathways were determined.. MI induced in Beagle dog was characterized by elevated ST-segment and increased CK-MB level in serum. Cardiac NLRP3 inflammasome was activated with elevated myocardial IL-1β and IL-18 concentrations mediated by ROS over-production and TXNIP over-expression in MI dogs. Additionally, pro-inflammatory cytokines induced impairment of cardiac JAK2-STAT3 inflammatory pathway and insulin signaling pathway in this model, resulting in down-regulation of cardiac PPAR-α expression, subsequently causing lipid metabolism disorders characterized by elevation of myocardial lipid concentrations. These abnormalities were attenuated by the treatment of STS and DI.. These data firstly demonstrated that cardiac NLRP3 inflammasome activation driven by cardiac ROS over-production and TXNIP up-expression resulted in impairment of the JAK2-STAT3 and insulin signaling pathways, leading to disorder of lipid metabolism in myocardial ischemic dogs through PPAR-α over-expression. STS and DI might target cardiac NLRP3 inflammasome in preventing MI injury.

Topics: Animals; Biomarkers; Carrier Proteins; Coronary Occlusion; Coronary Vessels; Creatine Kinase, MB Form; Disease Models, Animal; Dogs; Drugs, Chinese Herbal; Electrocardiography; Inflammasomes; Janus Kinase 2; Lipid Metabolism; Male; Myocardial Ischemia; Phenanthrenes; PPAR alpha; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor

Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, a well-known Chinese medicine for treating cardiovascular disorders. Cardiomyocyte apoptosis plays a major role in the development of cardiovascular diseases. The present study was designed to investigate the effects of STS on cardiomyocyte apoptosis induced by in vivo acute myocardial infarction (MI) in adult rats and by in vitro H2O2-treated neonatal rat ventricular myocytes. In MI rats, STS significantly reduced the infarct sizes, the blood lactate dehydrogenase (LDH) level, and the number of apoptotic cardiomyocytes in the infarcted hearts. In the in vitro study, STS reversed the decreased effect of cell viability induced by H2O2. In addition, STS also markedly inhibited H2O2-induced cardiomyocyte apoptosis. C-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) and p38 MAPK are classic oxidative stress-activated protein kinases. Our further mechanistic study revealed that increased JNK phosphorylation stimulated by H2O2 was abolished by STS treatment. In conclusion, inhibition of JNK activation plays a significant role in cardioprotective effects of STS.

Topics: Animals; Animals, Newborn; Apoptosis; Cardiotonic Agents; Cell Survival; Cells, Cultured; Drugs, Chinese Herbal; Enzyme Activation; Heart Ventricles; Hydrogen Peroxide; JNK Mitogen-Activated Protein Kinases; Male; Myocardial Infarction; Myocardial Ischemia; Myocytes, Cardiac; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phenanthrenes; Phosphorylation; Rats; Rats, Sprague-Dawley