Differential Expression of MMPs and TIMPs in Moderate and Severe Heart Failure in a Transgenic Model

Abstract

Background Altered expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) accompanies the development of heart failure (HF). However, changes in MMP and TIMP protein levels or activity during the progression from compensated to decompensated failure remains incompletely examined. Methods and Results Transgenic mice (Tg) with cardiac-specific overexpression of tumor necrosis factor-α (TNF1.6) develop a sex-related, progressive cardiac dilation and HF. Echocardiographic measures were used to categorize HF severity in male (M) and female (F) Tg and wild-type (WT) mice between 4 and 50 weeks of age. Cardiac TIMPs-1, TIMPs-2, and MMP-3 (enzyme-linked immunosorbent assay), and potential (APMA-activated) MMP-9 activity were measured at similar ages. In situ zymography assessed tissue gelatinase activity. Systolic function, ventricular dimensions, and presence of pleural effusions identified severe HF in younger M Tg mice (by 18 weeks) and older F Tg (>34 weeks). Regardless of age, sex, or HF severity, Tg mice expressed significantly more TIMP-1 (Tg 119–193 pg/mg vs. WT 13–24 pg/mg, P < .001) and potential MMP-9 activity (Tg 0.41–0.58 ng/mg vs. WT 0.015–0.028 ng/mg, P < .002). M Tg expressed elevated MMP-3 (4 weeks, 0.16 ± 0.1 ng/mg protein vs. WT 0.04 ± 0.01 ng/mg, P < .003), which increased with age and HF severity (18 weeks, 0.51 ± 0.3 ng/mg P < .01). F Tg showed no increase in MMP-3 at 4 weeks but a progressive increase with age and HF severity (18 weeks 0.09 ± 0.04 ng/mg, P < .02 vs. Tg M or WT; 34 weeks 0.13 ± 0.02 ng/mg, P < .001 vs. WT). To test the hypothesis that increased MMP-3 may differentially activate MMP-9 in M Tg, in situ zymography was performed and revealed a significant increase in gelatinase activity in M Tg mice relative to both WT and F Tg. Conclusion MMP-3 may regulate activation of MMP-9/gelatinase, the progression of cardiac remodeling, and development of decompensated heart failure.