leukotriene-b4 and Heart-Failure

Cardiac local renin-angiotensin system plays an important role in the development of heart failure and left ventricular (LV) remodeling. We previously reported that hydrogen sulfide (H2S), an endogenous gaseous mediator, regulates renin synthesis and release in juxtaglomerular cells. The present study was designed to investigate whether H2S can protect against isoproterenol (ISO)-induced heart failure via inhibition of local renin activity in rat hearts.. In the present study, we found that an injection of ISO (150 mg/kg) significantly increased plasma lactate dehydrogenase level and hypertrophy index and impaired LV end diastolic pressure. Treatment with NaHS (an H2S donor, 0.056 mg/kg, daily) 3 days before and 2 weeks after the ISO injection attenuated the development of heart failure. Histological staining showed that NaHS decreased ISO-induced collagen deposition. Moreover, NaHS treatment reversed ISO-induced renin elevation in both plasma and LVs. Immunostaining analysis indicated that renin expression co-localized with mast cells in the ventricular tissues. Mast cell counts showed that NaHS treatment decreased the number of degranulated mast cells in cardiac tissue due to down-regulation of leukotriene A4 hydrolase protein expression and leukotriene B4 level. In addition, NaHS treatment also inhibited forskolin-induced renin degranulation from HMC-1.1 mast cells by lowering intracellular cAMP level.. This study provides evidence for a new pathway in H2S-induced cardioprotection against heart failure development.. For the first time, we demonstrated that H2S might protect heart during heart failure by suppression of local renin level through inhibition of both mast cell infiltration and renin degranulation.

Topics: Animals; Cardiotonic Agents; Cell Line; Collagen; Epoxide Hydrolases; Female; Heart Failure; Heart Ventricles; Hydrogen Sulfide; Isoproterenol; L-Lactate Dehydrogenase; Leukotriene B4; Mast Cells; Myocardium; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Ventricular Pressure

Chinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation.. DanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation.. A novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand-receptor interaction, calcium-signaling pathway, and aminoacyl-tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP.. The combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.

Topics: Animals; Cardiotonic Agents; Cyclooxygenase 1; Cyclooxygenase 2; Drugs, Chinese Herbal; Epoprostenol; Heart Failure; Leukotriene B4; Male; Medicine, Chinese Traditional; Panax notoginseng; Phytotherapy; Rats, Sprague-Dawley; Receptors, Leukotriene B4; Salvia miltiorrhiza; Thromboxane B2