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MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition.

Authors: Li, H  Simon, H  Bocan, TM  Peterson, JT 
Citation: Li H, etal., Cardiovasc Res. 2000 May;46(2):298-306.
Pubmed: (View Article at PubMed) PMID:10773234

OBJECTIVE: Determine the effect of a matrix metalloproteinase inhibitor (MMPi) and angiotensin converting enzyme inhibitor (ACEi) on collagen, MMP, tissue inhibitors of MMPs (TIMPs) expression in the spontaneously hypertensive heart failure (SHHF) rat. METHODS: Six groups were tested: normotensive 9- and 13-month-old Wistar-Furth (WF) rats, 9-month-old SHHFs (compensatory hypertrophy), 13-month-old SHHFs with HF, and 13-month-old SHHFs orally administered with either an MMPi (PD166793, 5 mgkg(-1)day(-1)) or ACEi (quinapril, 10 mgkg(-1)day(-1)) for 4 months. Collagen volume fraction was assessed histomorphometrically. Left ventricular (LV) mRNA [MMP-1,-2,-3,-7,-9,-11,-13,-14; TIMP-1,-2,-3,-4; and collagen alpha1(I) and alpha1(III)] and protein (MMP-2 and MMP-9 zymographic activity; Western blot analysis of MMP-13, and TIMP-1,-2,-4) levels could be quantified. RESULTS: Collagen mRNA levels were elevated in SHHFs compared to age-matched controls, but collagen volume fraction was elevated only in 13-month-old SHHFs (approximately 2x). Only MMP-2 mRNA levels increased significantly with HF. However, MMP-2 and MMP-9 zymographic activity, and MMP-13 protein levels increased. TIMP-1 and TIMP-2 mRNA and protein levels increased, and TIMP-4 protein levels decreased in SHHFs vs. controls. Both drug treatments reduced LV dilation; preserved systolic function; and normalized MMP/TIMP expression. Both drug treatments also reduced collagen volume fraction, but only quinapril reduced collagen mRNA levels and LV hypertrophy. CONCLUSIONS: The divergent effect of MMPi and ACEi on collagen mRNA levels and hypertrophy indicate that drug efficacy is mediated by different pathways in the SHHF rat.


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CRRD Object Information
CRRD ID: 2290467
Created: 2008-03-13
Species: All species
Last Modified: 2008-03-13
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.