Circulation. 2001;104:826-831
doi: 10.1161/hc3401.093154
doi: 10.1161/hc3401.093154
(Circulation. 2001;104:826.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor
From Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Affairs Medical Center (N.S., M.L.C., K.M.K., D.L.M.), and Department of Molecular and Cellular Biology (F.J.D.), Baylor College of Medicine, Houston, Tex; Division of Cardiology, UCLA School of Medicine, Los Angeles, Calif (W.R.M.); and Department of Surgery, Cardiothoracic Research, Medical University of South Carolina, Charleston (F.G.S.).
Reprint requests to Douglas L. Mann, MD, Cardiology Research (151C), VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu
Background— The mechanisms responsible for tumor necrosis factor (TNF)–induced LV structural remodeling in the adult heart are not known.
Methods and Results— We generated a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF that develop progressive LV dilation/remodeling from 4 to 12 weeks of age. During the early phases of LV structural remodeling, there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded to a decrease in total myocardial fibrillar collagen content. As the MHCsTNF mice aged, there was a significant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP activity and myocardial fibrillar collagen content were related to a time- dependent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)-1 levels, resulting in a significant time-dependent decrease in the MMP activity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechanism for the increase in myocardial fibrosis, we also measured levels of TGF-ß1 and TGF-ß2 protein levels, which were shown to be significantly elevated in the hearts of the MHCsTNF mice.
Conclusions— Our results suggest that progressive time-dependent changes in the balance between MMP activity and TIMP activity are responsible, at least in part, for the spectrum of TNF-induced changes in the myofibrillar collagen content that occur during LV structural remodeling in the MHCsTNF mice.
Key Words: heart failure • genes • growth substances • collagen • tumor necrosis factor
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