Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0264733 (ventricular dilatation)
 2,163 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. TNF-alpha initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-alpha has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-alpha expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1beta, transforming growth factor-beta, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1beta were significantly further upregulated in R2KO mice. TNF-alpha is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI.
 ...
PMID:Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. 1741 8

Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-alpha are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-alpha with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-alpha inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-alpha antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-alpha has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.
 ...
PMID:TNF-alpha inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. 1966 42