Abstract:
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-beta(1) and TGF-beta(2) 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.
journal_name
Circulationjournal_title
Circulationauthors
Sivasubramanian N,Coker ML,Kurrelmeyer KM,MacLellan WR,DeMayo FJ,Spinale FG,Mann DLdoi
10.1161/hc3401.093154subject
Has Abstractpub_date
2001-08-14 00:00:00pages
826-31issue
7eissn
0009-7322issn
1524-4539journal_volume
104pub_type
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