| Background and objective: Although myocardial remodeling is accompanied bychanges in the cellular constituents of the left myocardium, significant alterations in thestructure and composition of the extracellular matrix (ECM) also occur. Moreover, it hasbecome increaseingly evident that the fribrillar collagen matrix of the myocardial ECMmay play a fundamental role in pathological myocardial remodeling processes with heartfailure. Therefore, identification and understanding of the biological system responsible forECM synthesis and degradation within the myocardium holds particular relevance. Matrixmetalloproteinases (MMPs) are endogenous family of zinc-dependent enzymes whichidentified to be responsible for matrix remodeling, the tissue inhibitors of MMPs(TIMPs) that bind to active MMPs and thereby regulate proteolytic activity. A number ofbioactive peptides and cytokines influence MMPs and TIMPs expression and activity. Forexample, in rat cardiac fibroblasts, the proinflammatory cytokine tumor necrosis factor-α(TNF-α) can activate the MMPs and inhibit the expression of TIMPs in vivo-effect thatwould be expected to activate ECM remodeling. Nuclear factor-kappa B (NF-KB) is animportant transcription factor that controls a number of genes involved in inflammation andimmune responses. Furthermore, the recent studies demonstrated that activated NF-KB innuclei could be detected in cardiac myocytes, endothelial cells and fibroblasts. NF-kBregulates expression of target genes including TNF-α and MMPs, in the other hand, TNF-αbinding to cell surface receptors results in NF-KB activation, p-adrenergic-blocking agentscarvedilol (Car) has been shown to reduce morbidity and mortality, andangiotensin-converting enzyme inhibitors (ACEI) fosinopril (Fos) has proved the benefiteffect on myocardial remodeling and improving cardiac function in chronic heart failure.Hower, the independent and combined effects of Car and Fos on myocardial MMP/TIMPand cytokines system in heart failure have not been demonstrated. Consequently, this studybased on the experimental model of chronic myocardial infarction in the rat, is aimed atunderstanding the effects of myocardial NF-KB activation and TNF-α expression onMMP/TIMP system, myocardial ECM remodeling and progressive heart failure, comparing the influence of both of Car and Fos as monotherapy and adjunctive treatment on activation and expression of MMP/TIMP system, TNF-a and NF-kB, and myocardial ECM remodeling.Methods: Myocardial infarction (MI) was induced in Wistar rat weighting 200g to 240g through ligation of the left anterior descending left coronary artery, treatment was started 24 hour after surgery .with placebo, Car (Img.kg-1.d-1), Fos (10mg.kg-1.d-1), or Car (1mg.kg-1.d-1) and Fos (10mg.kg-1.d-1) administered by gavage twice a day. Sham-operated rats were used as the control group. Hemodynamic studies were performed respectively on weeks 4, 8, and 12 after coronary artery ligation. After hemodynamic measurement, heart were excised and dissected into right and left ventricle including septum which were weighed individually. Immunohistochemistry for observing the distributions of TNF-a, MMP-8, MMP-9 and TIMP-1 in cardiac tissue; Western blotting for semi-quantification of TNF-a, MMP-8, MMP-9 and TIMP-1; RT-PCR for analysis of TNF-a; Gelatin Zymography for myocardial MMP gelatinlytic activity; Electromobility shift assay (EMSA) for NF-KB activity; Picrosirius red staining using image analysis software calculated collagen content; Pathologic and morphologic studies on cardiac tissue were observed by optical and transelectronic microscope.Results: 1. There were no differences in infarction size among the groups (35%-55%). Compared with sham-operated group, MI rats showed Left ventricular end-diastolic pressure (LVEDP) significant increased, and mean artery pressure (MAP), left ventricular systolic pressure (LVSP), maximum rate of pressure rise (+dp/dtmax) and m...
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