Abstract

Observational studies and inhibition studies indicate that matrix metalloproteinases (MMPs) participate in the left ventricular remodeling process. The Lee laboratory has demonstrated that broad spectrum MMP inhibition in mice attenuates ventricular dilation following myocardial infarction. However, the roles of specific MMPs in mediating this process are unclear. MMP-9, also known as gelatinase B or 92kDa gelatinase, is an MMP that is prominently overexpressed following acute myocardial infarction. A transgenic mouse with targeted deletion of the MMP-9 gene will be used to examine three Specific Aims highly relevant to the development of congestive heart failure following MI.
The Specific Aims of this proposal are. 1 . Explore the effects of targeted deletion of the MMP-9 gene on LV remodeling following experimental myocardial infarction. 2. Explore the effects of targeted deletion of the MMP-9 gene on LV hemodynamics following experimental myocardial infarction. 3. Explore the role of MMP-9 in localizing neutrophil infiltration and contributing to LV remodeling following ischemia/reperfusion.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010337-03
Application #
6536721
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Commarato, Michael
Project Start
2002-05-01
Project End
Budget Start
2002-05-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$44,212
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Dozier, S; Escobar, G P; Lindsey, M L (2006) Matrix metalloproteinase (MMP)-7 activates MMP-8 but not MMP-13. Med Chem 2:523-6
Lindsey, Merry L; Escobar, G Patricia; Mukherjee, Rupak et al. (2006) Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113:2919-28
Lindsey, Merry L; Escobar, G Patricia; Dobrucki, Lawrence W et al. (2006) Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction. Am J Physiol Heart Circ Physiol 290:H232-9
Lindsey, Merry L; Goshorn, Danielle K; Squires, Christina E et al. (2005) Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function. Cardiovasc Res 66:410-9
Lindsey, Merry L (2004) MMP induction and inhibition in myocardial infarction. Heart Fail Rev 9:7-19
Lindsey, Merry L; Yoshioka, Jun; MacGillivray, Catherine et al. (2003) Effect of a cleavage-resistant collagen mutation on left ventricular remodeling. Circ Res 93:238-45
Lindsey, Merry L; Mann, Douglas L; Entman, Mark L et al. (2003) Extracellular matrix remodeling following myocardial injury. Ann Med 35:316-26
Lindsey, Merry L; Gannon, Joseph; Aikawa, Masanori et al. (2002) Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 105:753-8