Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor

Background-The mechanisms responsible for tumor necrosis factor (TNF)-induc ed LV structural remodeling in the adult heart are not known. Methods and Results-We generated a line of transgenic mice (MHCsTNF) with c ardiac restricted overexpression of TNF that develop progressive LV dilatio n/remodeling from 4 to 12 weeks of age. During the early phases of LV struc tural remodeling, there was a significant increase in total matrix metallop roteinase (MMP) activity that corresponded to a decrease in total myocardia l fibrillar collagen content. As the MHCsTNF mice aged, there was a signifi cant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP acti vity and myocardial fibrillar collagen content were related to a time- depe ndent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)- 1 levels, resulting in a significant time-dependent decrease in the MMP act ivity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechani sm 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 significan tly 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 leas t in part, for the spectrum of TNF-induced changes in the myofibrillar coll agen content that occur during LV structural remodeling in the MHCsTNF mice .