| Background and Aim：The neurohormonal regulatory mechanisms was activated after myocardial infarction(myocardial infarction, MI), inflammation and cytokines induced changes in myocardial cellsand mesenchymal morphology, leading to ventricular remodeling, the development of cardiacmorphology and hemodynamics abnormalities, namely heart failure (heart failure, HF). How toslow down and reverse ventricular remodeling after myocardial infarction is the key toprevention and treatment of heart failure after myocardial infarction. Although the mechanismsof ventricular remodeling were multifactorial, the consensus was that the inflammation is animportant part of ventricular remodeling. Nuclear factor-κB (nuclear factor-kappa-B, NF-κB) isa nuclear transcription factor of multi-directional regulation, previous studies showed thatactivation of NF-κB induced by myocardial infarction, the expression of inflammatory cytokineswas increased, thereby aggravated the inflammatory response, and activation of NF-κB may alsobe involved in the other physiological and pathological processes including changes inmyocardial extracellular matrix. But the impact of inhibition of NF-κB activation on the cardiacfunction and ventricular remodeling after myocardial infarction remains to be further elucidated.In this study, a rat model of myocardial infarction (MI model for short) was successfullyestablished by ligation of the left anterior descending (LAD) coronary artery. NF-κB signalingpathway inhibitor-pyrrolidine dithiocarbamate (PDTC) was used to inhibit activation of NF-κBafter myocardial infarction, in order to study the impact of inhibition of NF-κB activation onventricular remodeling and cardiac function after myocardial infarction in rats, and to explore themechanisms. Methods:A rat model of MI model was established by ligation of the left anterior descending (LAD)coronary artery.24hours later the survivals were randomly divided into two groups: myocardialinfarction (MI) group and the experimental group (PDTC group); and the sham group (SH group)was established as a blank control. The next day after surgery, the experimental group wasinjected intraperitoneally with PDTC100mg/kg once daily, SH group and the MI group wereinjected intraperitoneally with the same dose of0.9%saline once daily, continuously until theend of the experimental observations. In the process of breeding,observed general situation andheart failure attack situation in the rat model. The study parameters were assessed1week,2weeks,4weeks following the establishment of MI model. Left ventricular size (left ventricularend-diastolic diameter and left ventricular end-systolic diameter, ie LVEDD and LVESD), leftventricular ejection fraction (EF) and left ventricular end-diastolic wall thickness (LVPWd) weremeasured by echocardiography. The rats were sacrificed to measure weight of body, heart andleft ventricular to calculate left ventricular mass index and cardiac mass index, myocardial tissuepathology by HE staining, myocardial fibrosis surrounding the infarct border zone by Massonstaining, and p65levels transferring from the infarct border zone to the nucleus which reflectsthe activation of NF-κB.Results:1. NF-κB was activated after myocardial infarction. Its activity reached the highest pointin1week, and was still significantly higher than the SH group in4weeks. NF-κBactivity of the PDTC group was significantly decreased in each time point comparedwith MI group.2. Compared with the SH groups, the MI group showed impaired cardiac function andventricular remodeling in1weeks, aggravated in4weeks; the study parameters ofPDTC group were better than the MI group in the same period.3. Compared with the SH group, left ventricular mass index of the MI group whichreflects left ventricular hypertrophy was gradually increased in the2weeks. Leftventricular mass index of the PDTC group was lower than the MI group in4weeks. 4. Compared with the MI group, myocardial infarct zone inflammation and the growth ofgranulation tissue of the PDTC group was inhibited in1week and2weeks.Comparison with the SH group in the2weeks and4weeks, tissue in myocardialinfarct zone of the MI group and PDTC group thinned, and was gradually replaced byfibrous scar, Cardiomyocyte in infarct border zone became hypertrophic, disorganized,and showed an increases matrix fibrosis. Structure of infarct border zone of the PDTCwas more improved than the MI group.5. Collagen deposition in myocardial tissue surrounding infarct border zone of the MIgroup was significantly increased compared with the SH group in4weeks. PDTC caninhibit collagen deposition in collagen deposition in myocardial tissue surroundinginfarct border zone.Conclusions:1. After myocardial infarction，NF-κB activity was significantly increased, reached apeak in1week, and then was gradually decreased, remained still higher than normallevels in4weeks. PDTC can inhibit the NF-κB activation in myocardial tissuesurrounding the infarct border zone after myocardial infarction.2. Ventricular remodeling after myocardial infarction was observed, including significantexpansion of the ventricular cavity, posterior wall thickness, myocyte disarray, stromalfibrosis, and aggravated with the extension of time. The treatment with PDTC wasproved to inhibit NF-κB activation to delay ventricular remodeling after myocardialinfarction in rats.3. PDTC treatment suppressed myocardial NF-κB activation to improve heart functionafter myocardial infarction. The effects may be related to reduction of the inflammatoryresponse and myocardial interstitial collagen deposition after myocardial infarction,which slow down ventricular remodeling. |
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