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

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.

• Authors: H Li, H Simon, T M Bocan, J T Peterson
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 46 Issue 2 Pg. 298-306 (May 2000) ISSN: 0008-6363 [Print] England
• PMID: 10773234 (Publication Type: Journal Article)

Chemical References

• (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

Topics

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