Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treats ischemic cardiomyopathy.

Abstract:

BACKGROUND:Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy. METHODS AND RESULTS:Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (n=8) or null virus as control vector (n=8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70+/-10 versus control 56+/-12 mmHg, P<0.05; maximum dP/dt 2697+/-842 versus 1622+/-527 mmHg/sec, P<0.01; minimum dP/dt -2900+/-917 versus -1195+/-593, P<0.001). Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0+/-0.7 versus control 14.4+/-0.4 mm, P<0.001; border-zone wall thickness 1.59+/-0.11 versus control 1.28+/-0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36+/-0.87 versus control 3.89+/-1.79 microg hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5+/-0.9 versus control 43.1+/-14.9 ng of MMP-1 activity, P<0.05). CONCLUSIONS:TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy. The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation.

journal_name

Circulation

journal_title

Circulation

authors

Jayasankar V,Woo YJ,Bish LT,Pirolli TJ,Berry MF,Burdick J,Bhalla RC,Sharma RV,Gardner TJ,Sweeney HL

doi

10.1161/01.CIR.0000138946.29375.49

subject

Has Abstract

pub_date

2004-09-14 00:00:00

pages

II180-6

issue

11 Suppl 1

eissn

0009-7322

issn

1524-4539

pii

110/11_suppl_1/II-180

journal_volume

110

pub_type

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