| Backgroud Ventricular tachycardial (VT) and ventricular fibrillation (VF) are major causes of mortality in patients after myocardial infarction (MI). There is evidence that sympathetic neural remodeling after MI plays an important role on ventricular arrhythmogenesis and provides an electrical substrate for VT/VF. Artemisinin is the active component of Artemisia annua L. This medicinal plant has been used as a remedy for fevers and chills for centuries in China. In the21st century, artemisinin was approved for the treatment and prevention of malaria by the world health organiziation(WHO). Moreover, it has been shown to possess immunology-regulation, anti-inflammatory and anti-fibrosi activities. The mechanism of artemisinin anti-inflammatory was related to its sesquiterpene lactone structure, which has the ability to inhibit the activation of of NF-kB signal pathway. Li et al reported that artesunate inhibits the lipopolysaccharide-induced production of TNF-a, IL-6and nitricoxide (NO) and decreases the expression of Toll-like receptor4(TLR4) and TLR9in macrophages. Xiong et al reported that artemisinin can ameliorate myocardial hypertrophy via inhibition of NF-kB signal pathway. Based on the anti-inflammatory effect of artemisinin, the present study was aimed at investigating whether artemisinin could ameliorate the progression of sympathetic remodeling and electrical remodeling after MI.Part I The mechanism and effect of artemisinin on the sympathetic remodeling following myocardial infarctionObjective The purpose of this study was to investigate whether artemisinin could ameliorate the progression of sympathetic remodeling and its related mechanism after MI.Methods Adult male Sprague Dawley rats were divided into a sham group (n=10) and MI groups treated either with artemisinin (75mg/kg/day, n=20) or vehicle (0.5%carboxymethyl cellulose, n=20)24hours after ligation of the left anterior descending coronary artery. Four weeks after MI, the rats were killed and the hearts were removed. In order to test the sympathetic remodeling and macrophage infiltration, we used Immunohistochemistry method. At the same time, we detect the protein of p-IKB α/IKB a、NGF、GAP43、TH expression by western blotting. At last, the TNF-α mRNA and IL-1β mRNA was tested by RT-PCR.Results Our results show that artemisinin significantly inhibited IL-1β mRNA and TNF-α mRNA expression and the infiltration of macrophages. Artemisinin significantly decreased the protein expression of p-IKB α/IKB α, NGF, GAP43, and TH compared with the control group, which was related to sympathetic nerve remodeling. In addition, the densities of both GAP-43and TH-immunoreactive nerves in the peri-infarct zone were significantly attenuated by artemisinin treatment(GAP43:2024.23±286.71um2/mm2vs3103.5±238.69um2/mm2, P<0.05).(TH:1995.46±243.48um2/mm2vs3113.25±402.61um2/mm2, P<0.05).Conclusion Artemisinin is able to inhibit sympathetic remodeling after MI, possibly through an anti-inflammatory effect. Part II The mechanism and effect of artemisinin on the electric conduction and inducibility of ventricular arrhythmias following myocardial infarctionObjective To investigate the mechanism and effect of artemisinin on the electric conduction and inducibility of ventricular arrhythmias following myocardial infarction.Methods We investigated the electrophysiological and arrhythmogenic effects of artemisinin therapy in experimental infarction model. Rats were subjected to MI operation by LAD ligation and randomly allocated to receive vehicle or artemisinin treatment. Electrophysiological study, histological examination, real-time PCR and western blotting were performed4weeks after MI.Results Programmed electrical stimulation (PES) showed a significant increased ventricular fibrillation threshold (VFT)(10±1.95V vs6±1.51V, P<0.05) and reduced the inducibility of ventricular arrhythmias (40%vs75%, P<0.05) in the artemisinin-treated group compared to vechicle-treated group. Under the pacing rate, the activation time was prolonged at infarct border zone in the vechicle treated group, but this prolongation was attenuated by the artemisinin treatment (13.23±1.73ms vs18.12±2.85ms, P<0.05). Histological study revealed that myocardial fibrosis and abnormal alterations of Connexin43including reduction and lateralization at the infarcted border zone were significantly attenuated by artemisinin treatment.Conclusion Artemisinin can reduce the inducibility of ventricular arrhythmias and increase the conduction velocity possiblely by anti-fibrosis and attenuation of Connexin43remodeling after MI. Part Ⅲ The mechanism and effect of artemisinin on the electrophysiology following myocardial infarctionObjective To investigate the mechanism and effect of artemisinin on the electrophys-iology following myocardial infarction.Methods We investigated the electrophysiological and arrhythmogenic effects of artemisinin therapy in experimental infarction model. Rats were subjected to MI operation by LAD ligation and randomly allocated to receive vehicle or artemisinin treatment. Electrophysiological study, western blotting were performed4weeks after MI.Results Programmed electrical stimulation (PES) showed prolonged ventricular effective refractory period (VERP)(58.46±5.41ms vs50.5±2.87ms, P<0.05) in artemisinin-treated group compared to vechicle-treated group. Under the difference pacing rate, the action potential duration was prolonged both at the vitro and vivo in the vechicle treated group, but this prolongation was attenuated by the artemisinin treatment. Moreover, the APD alternans was increased and the threshold heart rate for alternans was reduced in the vechicle treated group, but these changes were attenuated by artemisinin treatment. Western blotting to test the channel protein, compared to sham group, the expression levels of KV4.2, Kir2.1, KchIP2, SERCA2a proteins were significantly decreased in the vechicle-treated group. In contrast, the expression levels of these proteins were restored in the artemisinin-treated group.Conclusion Artemisinin can attenuate of electrical remodeling and reduce the electrophysiological heterogeneity after MI possiblely by up-regulation of ionic channel protein. |
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