Abstract
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.
Footnotes
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This work was supported by National Institutes of Health Grants HL59165, PO1 HL48788-08, and P20 RR16434 and a merit award from the Veterans Affairs Health Administration.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.104455.
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ABBREVIATIONS: MI, myocardial infarction; LV, left ventricle; MMP, matrix metalloproteinase; MMPi, MMP pharmacological inhibition; TIMP, tissue inhibitor of matrix metalloproteinase; PD200126 (formerly PD166793), (s)-2-(4-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
- Received March 15, 2006.
- Accepted June 2, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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