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


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.
Jayasankar
Vasant
V
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa 19104-4283, USA
Woo
Y Joseph
YJ
Bish
Lawrence T
LT
Pirolli
Timothy J
TJ
Berry
Mark F
MF
Burdick
Jeffrey
J
Bhalla
Ramesh C
RC
Sharma
Ram V
RV
Gardner
Timothy J
TJ
Sweeney
H Lee
HL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003673:Defective Viruses / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D005813:Genes, Synthetic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D008026:Ligation; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000502:physiology*
D061965:Matrix Metalloproteinase Inhibitors; D011993:Recombinant Fusion Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D006909:Hydroxyproline