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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 6, 2006; DOI: 10.1124/jpet.106.104455

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Received for publication March 16, 2006.
Revised June 1, 2006.
Accepted for publication June 2, 2006.

Chronic Matrix Metalloproteinase Inhibition Following Myocardial Infarction in Mice: Differential Effects on Short and Long Term Survival

Francis G. Spinale 1*, G. Patricia Escobar 1, Jennifer W. Hendrick 1, Leslie L. Clark 1, Sarah S. Camens 1, Joseph P. Mingoia 1, Christina G. Squires 1, Robert E. Stroud 1, John S. Ikonomidis 1

1 Medical University of South Carolina

* Address correspondence to: E-mail: wilburnm{at}musc.edu

Abstract

Left ventricular (LV) remodeling occurs following myocardial infarction (MI) and the matrix metalloproteinases (MMPs) contribute to adverse LV remodeling following MI. Short term pharmacological MMP inhibition (MMPi;days to weeks) in animal models of MI have demonstrated a reduction in adverse LV remodeling. However, the long term effects (months) of MMPi on survival and LV remodeling following MI have not been examined. MI was induced in adult mice (n=131) and at 3 days post-MI assigned to MMPi (MI-MMPi:PD200126, 7.5 mg/day/PO, n=64) or untreated (MI only, n=67). Unoperated mice (n=16) served as controls. The median survival in the MI only group was 5 days whereas median survival was significantly greater in the MI-MMPi group at 38 days (p<0.05). However, with prolonged MMPi (>120 days), a significant divergence in the survival curves occurred in which significantly greater mortality was observed with prolonged MMPi (p<0.05). LV echocardiography at 6 months revealed LV dilation in the MI-only and MI-MMPi groups (154±14, 219±24 µL) compared to control (67 ± 4 µL, p<0.05) with a greater degree of dilation in the MI-MMPi group (p<0.05). MMPi conferred a beneficial effect on survival early post-MI, but prolonged MMPi (>3 months) was associated with higher mortality and adverse LV remodeling. These unique results suggest that an optimal temporal window exists with respect to pharmacological interruption of MMP activity in the post-MI period.


Key words: matrix, myocardial function, myocardial infarction, myocardial remodeling, myocardial structure, remodeling


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