Experimental Heart Failure Models of Cytokine Overexpression
Heart failure secondary to systolic dysfunction is a progressive cardiovascular disease that affects over 5 million people in the U.S. While the initial cause of heart failure in most patients is myocardial damage, the heart usually accommodates to the damage. However, over time, the heart remodels with the development of cardiac dilatation, cellular hypertrophy, cell slippage, diminished adrenergic responsiveness, apoptosis and extracellular matrix fibrosis and restructuring. Over the past decade, there has been a substantive increase in our knowledge of the pathobiology of the development of the heart failure phenotype. This increased knowledge has in part been attributable to advances in the sciences of cell and molecular biology and their application to studies of the failing human heart. However, our improved understanding of the molecular and cellular events leading to the development of heart failure and in particular the transition from compensated to de-compensated myocardial function can also be attributed to studies of new and novel animal models. Indeed, it is studies in animal models that have contributed seminal information regarding the fundamental role of the pro-inflammatory cytokines in the development of the heart failure phenotype. This Chapter will review in detail the observations from animal models that have supported the “Cytokine Hypothesis” of heart failure and will detail how animal models of cytokine over-expression have provided novel experimental platforms for evaluating the efficacy of anti-cytokine pharmacotherapy.
KeywordsHeart Failure Extracellular Matrix Remodel Soluble Tumor Necrosis Factor Receptor Heart Failure Model Adrenergic Responsiveness
Unable to display preview. Download preview PDF.
- 7.Bozkurt B, Kribbs SB, Clubb FJ, Jr., Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–1391.PubMedCrossRefGoogle Scholar
- 11.Kubota T, Miyagishima M, Bounoutas GS, Kadokami T, Watkins SC, McTiernan CF, Feldman AM. Over-expression of tumor necrosis factor-a activates both anti-and pro-apoptotic pathways in the myocardium. J Mol Cell Cardiol 2000;in pressGoogle Scholar
- 12.Shusterman V, Usiene I, Aysin B, Feldman AM, London B. Slow rhythm destabilization precedes initiation of ventricular arrhythmias in a TNF-? Mouse model of congestive heart failure. NASPE in press: (Abstract)Google Scholar
- 22.Lefebvre V, Peeters-Joris C, Vaees G. Production of gelatin-degrading matrix metalloproteinases (`type IV collagenases’) and inhibitors by articular chondrocytes during their dedifferentiation by serial subcultures and under stimulation by interleukin-1 and tumor necrosis factor alpha. Biochim Biophys Acta 1991;1094:8–18.PubMedCrossRefGoogle Scholar
- 25.Kadokami T, McTiernan CF, Kubota T, Feldman AM. Long term estradiol treatment improves survival in male mice with heart failure induced by cardiac specific TNF-expression. Circulation 102:II-72 (Abstract)Google Scholar
- 34.Lin H, Chensue SW, Strieter RM, Remick DG, Gallagher KP, Bolling, SF, Kunkel SL. Antibodies against tumor necrosis factor prolong cardiac allograft survival in the rat. Journal of Heart & Lung Transplantation 1992;11:330–335.Google Scholar
- 37.Kurrelmeyer KM, Michael LH, Baumgarten G, Taffett GE, Peschon JJ, Sivasubramanian N, Entman ML, Mann DL. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 2000;97:5456–5461.PubMedCrossRefGoogle Scholar
- 39.Kadokami T, Kubota T, Bounoutas GS, McTiernan CF, Feldman AM. Soluble tumor necrosis factor receptor differentially regulates cardiac cytokine gene expression in mice with lipopolysaccharide-induced endotoxemia. Circulation 1999;100:I-16 (Abstract)Google Scholar
- 44.Spinale FG, Coker ML, Krombach SR, Mukherjee R, Hallak H, Houck WV, Clair MJ, Kribbs SB, Johnson LL, Peterson JT, Zile MR. Matrix metalloproteinase inhibition during the development of congestive heart failure. Effects on left ventricular dimensions and function. Circ Res 1999;85:364–376.PubMedCrossRefGoogle Scholar
- 45.Li YY, Feng YQ, Kadokami T, McTiernan CF, Feldman AM. Modulation of matrix metalloproteinase activities remodels myocardial extracellular matrix in TNFs transgenic mice. Circulation 1999; 100:I-752 (Abstract)Google Scholar
- 46.Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy: role of metalloproteinases and pyridinoline cross links. American Journal of Physiology 1996;148:1639–1648.Google Scholar