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Effects Of Ghrelin On Neural Remodeling And Ventricular Remodeling In Rats With Myocardial Infarction And The Mechanisms Study

Posted on:2011-03-19Degree:DoctorType:Dissertation
Country:ChinaCandidate:M J YuanFull Text:PDF
GTID:1224360305483517Subject:Internal Medicine
Abstract/Summary:PDF Full Text Request
BackgroudPatients occurred acute myocardial infarction have high risk with sudden cardiac death. Ventricular remodeling after MI lead to reduced cardiac function and heart failure. In additional to ventricular remodeling, MI also induces electrical remodeling and cardiac nerve remodeling; they constitute the post-MI substrate of arrhythmia. It has been demonstrated that heterogeneous cardiac nerve sprouting and sympathetic hyperinnervation play important roles in arrhythmogenesis and sudden cardiac death in both human patients and animal models of MI. Although the etiology of post-MI ventricular arrhythmias remains incompletely understood, increased sympathetic drive and altered ventricular conduction are clearly contributoy, and the cardiac function following MI is considered as an independent predictor of SCD. Thus, further studies are needed to elucidate the mechanisms underlying neural remodeling and ventricular remodeling, and to prevent the process will decrease the incidence of SCD after MI.Ghrelin, a newly discovered endogenous hormone that is produced by the stomach, and synthetic peptides have been identified recently as potent growth-hormone secretagogues. Apart from appetite inducing effects and growth hormone releasing, recently studies demonstrated its cardioprotective effect, including anti-inflammation, vasodilatory and regulate cardiac cell energy. In this study, we attempted to discuss the effect of ghrelin after myocardil infarction. The study was divided into three parts as bellow.PartⅠ:ghrelin inhibits cardiac neural remodeling after myocardial infarction in ratsObjective:Ghrelin is a newly discovered peptide as an endogenous ligand for the growth hormone secretagogue receptor, and has been demonstrated to exert beneficial effect in the cardiovascular system. In the present study, we investigated whether ghrelin administration could inhibit cardiac neural remodeling and sympathetic hyperinnervation after myocardial infarction (MI). Methods:Sprague-Dawley rats underwent coronary ligation to induce MI and received rat ghrelin (100μg/kg SC BID) or saline (control). Four weeks after treatment, rats were sacrificed. We examined the expression of nerve growth factor and never markers in the infarcted border and non-infarcted left ventricular free wall, as well as the mRNA expressions of proinflammatory mediators. We also examined the NF-κBp65 protein and I-κBαprotein levels by western blot analysis. Results:Compared to the control group, ghrelin administration significantly decreased the density of nerve fibers with positive immunostaining for GAP43 and TH, and decreased NGF mRNA and protein levels. Ghrelin also significantly suppressed interleukin-1β, tumor necrosis factor-α, and endothelin-1 mRNA expression, and inhibited NF-κB activation. In the MI rats, the mRNA expression of ET-1 at the non-infarcted zones had a significantly positive correlation with the NGF protein levels. Conclusion:Treatment with ghrelin inhibited neural remodeling and sympathetic hyperinnervation, the process that may be associated with the inhibition of proinflammatory response and NGF signaling.PartⅡ:the expression of nerve growth factor receptors after myocardial infarction in ratsObjective:Nerve growth factor (NGF) regulates myocardial sympathetic innervation and induces sympathetic nerve hyperinnervation after myocardial infarction. Its neutrophic effects by binding to specific cell surface receptors, including the high-affinity receptor tyrosine kinase A(TrkA) and the NGF low-affinity receptor P75NTR. However, it is unclear whether the TrkA and P75NTR are altered after acute myocardial infarction. The aim of this study was to determine the dynamic change of NGF receptor expression from 1 days to 30 days after myocardial infarction in the rat. Methods:Rats were subjected to MI and killed 1,7,30 days after MI, the sham operated rats were considered as control. TrkA and P75NTR mRNA expression and protein levels in the infarcted border myocardium were measured by real-time PCR and western-blot. Results:We found that after MI, both P75NTR mRNA expression and protein levels showed no significant change when compared with control group at all time points, whereas TrkA expression decreased at day 7 after MI and continued to decrease at day 30. Conclusion:A specific temporal pattern of TrkA/p75NTR occurred in post-MI rats, the p75NTR may not be crucial mediates sympathetic innervation after MI.PartⅢ:the influence of ghrelin on ventricular remodeling and cardiac function after myocardial infarction in ratsObjective:To investigate the effect and potential mechanism of ghrelin on ventricular remodeling after acute myocardial infarction in rats. Methods:Sprague-Dawley rats underwent coronary ligation to induce MI or sham surgey and received rat ghrelin (100μg/kg SC BID) or saline 7 days after operation.4 weeks after treatment, echocardiography and hemodynamic examination were performed, IL-1βand TNF-a was detected by ELISA, TUNEL assay to determine the apoptotic cardiac cell, mRNA and protein expression of MMP-2 and MMP-9 were detected by real-time quantitative PCR and western-blot analysis. Results:Compared to the MI-saline group, ghrelin treatment significantly decreased left ventricular (LV) remodeling in post-MI rats, as indicated by increased LV maximum rate of pressure, LV fractional shortening, scar thickness; and decreased LV end-diastolic pressure, LV end-systolic diameter, LV end-diastolic diameter and cardiocytocytes apoptosis. Moreover, ghrelin inhibited inflammatory response, as shown by decreased level of interleukin (IL)-1βand tumor necrosis factor-α(TNF-α). Subsequently, the expression of matrix metalloproteinase (MMP)-2 and MMP-9 were also inhibited by ghrelin injection. Conclusion:Ghrelin alleviates LV dydfunction and ventricular remodeling in post-MI rats, these beneficial effects of ghrelin may result from an inhibition of inflammatory response.
Keywords/Search Tags:Myocardial infarction, Nerve remodeling, Ventricular remodeling, Ghrelin, Inflamation response
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