PT  - JOURNAL ARTICLE
AU  - Francis G. Spinale
AU  - G. Patricia Escobar
AU  - Jennifer W. Hendrick
AU  - Leslie L. Clark
AU  - Sarah S. Camens
AU  - Joseph P. Mingoia
AU  - Christina G. Squires
AU  - Robert E. Stroud
AU  - John S. Ikonomidis
TI  - Chronic Matrix Metalloproteinase Inhibition Following Myocardial Infarction in Mice: Differential Effects on Short and Long-Term Survival
AID  - 10.1124/jpet.106.104455
DP  - 2006 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 966--973
VI  - 318
IP  - 3
4099  - http://jpet.aspetjournals.org/content/318/3/966.short
4100  - http://jpet.aspetjournals.org/content/318/3/966.full
SO  - J Pharmacol Exp Ther2006 Sep 01; 318
AB  - Left ventricular (LV) remodeling occurs after myocardial infarction (MI), and the matrix metalloproteinases (MMPs) contribute to adverse LV remodeling after 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 after MI have not been examined. MI was induced in adult mice (n = 131) and, at 3 days post-MI, assigned to MMPi [MI-MMPi: (s)-2-(4-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (PD200126), 7.5 mg/day/p.o., 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 and 219 ± 24 μl) compared with 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. The American Society for Pharmacology and Experimental Therapeutics