Protective Effects Of A NF-κB Inhibitor, Pyrolidine Dithiocarbamate, On Heart Failure Induced By Myocardial Ischemia In Rats

Background and objective:Inflammation is involved in the pathogenesis of cardiovascular diseases, especially in the ischemic heart disease, including cardiac infarction, by causing myocardial damage, engaging into healing and fibrosis, leading to progressive impairment of cardiac function. Nuclear factor (NF)-κB has an important role in regulating inflammatory responses, which augments the expression of various inflammatory factors, consequently leads to cardiac injury. Monocyte chemoattractant protein (MCP)-1 is one of major chemokines, which may play an important role in the NF-kB-mediated effects by inducing inflammation. In this experiment, we observed the effect of NF-κB inhibition, using a NF-kB inhibitor (pyrrolidine dithiocarbamate, PDTC), on cardiac injury by ischemia and subsequent heart failure, the mechanisms underlying the protective of PDTC were also investigated.Methods:1. The cardiac injury models were established by hypodermic injection of high dose of isoprenaline (ISO) in rats.2. Rats were divided into control group, experimental group, treated group-1 and treated group-2.3. The expressions of cardiac NF-kB, MCP-1 mRNA and the plasma MCP-l levels were checked by immunohistochemistry, RT-PCR and ELISA.4. Cardiac function was determined by echocardiography, cardiac pathogenic states were also checked in this study.Results :1. The cardiac injury models were successfully established by hypodermic injection of high dose of isoprenaline (>85mg/kg ) in rats.2. PDTC down-regulated myocardial NF-κB, MCP-1 mRNA expressions and plasma MCP-1 levels in both treated group-1 and treated group-2. 3. Pre-treatment with PDTC alleviated myocardial inflammation and injury. As compared with control, PDTC decreased left ventricular end-systolic dimension (LVESD), increased percentage of ejection fraction after treatment for 14 days. However, after occurrence of ischemic injury, the application of PDTC, even in the early stage, could not alleviate cardiac necrotic area. PDTC could delay the replacement of the damaged myocardium with granulation tissue, depress capillary density in the border area of necrosis and decrease myofibroblast accumulation in the zone of necrosis. The ratio of ventricular aneurysm formation in treated group-2 was higher than experimental group. On day 28, the left ventricular functions in treated group-2 were worse than that in experimental group.Conclusions:1. Pretreatment with PDTC decreases myocardial ischemic injury induced by high dosage of ISO in rats. However, after occurrence of ischemic injury, even in the early stage, application of PDTC is harmful to heart.2. PDTC might have some protective effects on heart by alleviating ventricular dilatation and heart failure induced by myocardial ischemic injury in rats, the protective effects may vary due to chronergy. The protective effect is ascribed to the protection of cardiac myocytes in the early stage of cardiac injury.3. The above-mentioned effects are related to the inhibitioin of myocardial NF-κB activity, myocardial MCP-1 mRNA expression and serum MCP-1 synthesis.