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

Cardiovasc Res. 2000 May;46(2):298-306. doi: 10.1016/s0008-6363(00)00028-6.

Abstract

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.

MeSH terms

  • Analysis of Variance
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Blotting, Northern / methods
  • Blotting, Western / methods
  • Collagen / analysis
  • Collagenases / analysis
  • Collagenases / metabolism
  • Enzyme Inhibitors / therapeutic use
  • Heart Failure / drug therapy
  • Heart Failure / enzymology*
  • Hydroxamic Acids / therapeutic use
  • Isoquinolines / therapeutic use
  • Male
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / analysis
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / analysis
  • Matrix Metalloproteinases / metabolism*
  • Myocardium / chemistry
  • Myocardium / enzymology*
  • Oligopeptides / therapeutic use
  • Quinapril
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WF
  • Tetrahydroisoquinolines*
  • Tissue Inhibitor of Metalloproteinase-1 / analysis
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / analysis
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Tissue Inhibitor of Metalloproteinases / analysis
  • Tissue Inhibitor of Metalloproteinases / metabolism*

Substances

  • (R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid
  • Angiotensin-Converting Enzyme Inhibitors
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Isoquinolines
  • Matrix Metalloproteinase Inhibitors
  • Oligopeptides
  • Tetrahydroisoquinolines
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinases
  • tissue inhibitor of metalloproteinase-4
  • Tissue Inhibitor of Metalloproteinase-2
  • Collagen
  • Collagenases
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinases
  • Mmp13 protein, rat
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Quinapril