Despite current therapeutic strategies to restore blood flow to the ischemic myocardium and limit infarct size, adverse left ventricular (LV) remodeling that progresses to congestive heart failure (CHF) remains a significant complication following myocardial infarction (MI). The extracellular matrix (ECM) is a key component in the remodeling process following an MI, and increases in collagen occur in the infarct area to replace necrotic myocytes and form a scar. The macrophage is a chronic inflammatory cell that mediates LV remodeling during the healing phase post-Ml. Macrophages are key producers of and reactors to matrix metalloproteinases (MMPs), a family of enzymes that regulate matrix turnover during this remodeling process. Several laboratories have demonstrated MMP participation in remodeling events, and inhibition or the targeted deletion of specific MMPs (particularly MMP-9) have beneficial effects following MI. Thus, an understanding of how macrophages and macrophage-derived MMPs -7 and -9 regulate the matrix-mediated healing process in response to an MI will provide insight into the mechanisms of LV remodeling. In addition, the growing concept of non-matrix regulated MMP proteolysis illustrates that primary MMP functions may be matrix-independent.
In Specific Aim 1, we will study the role(s) of macrophages in early LV remodeling using mice with a targeted deletion of monocyte chemotactic protein-1 (MCP-1).
This aim will expand on preliminary work demonstrating a critical role for the macrophage in infarct remodeling.
Specific Aim 2 will examine the functional role of macrophage-specific overexpression of MMP-7 and MMP-9 on macrophage functions and remodeling events. Finally, in Specific Aim 3, we will use the emerging technology of proteomics to identify novel non-matrix MMP substrates in the macrophage that may play a role in LV remodeling. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075360-05
Application #
7248061
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$351,756
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Sourdon, Joevin; Keceli, Gizem; Lindsey, Merry L et al. (2018) Death of an antioxidant brings heart failure with preserved ejection fraction to life: 5-oxoproline and post-ischaemic cardio-renal dysfunction. Cardiovasc Res 114:1819-1821
Lindsey, Merry L; Mouton, Alan J; Ma, Yonggang (2018) Adding Reg3? to the acute coronary syndrome prognostic marker list. Int J Cardiol 258:24-25
Brooks, Heddwen L; Lindsey, Merry L (2018) Guidelines for authors and reviewers on antibody use in physiology studies. Am J Physiol Heart Circ Physiol 314:H724-H732
Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838
Ma, Yonggang; Mouton, Alan J; Lindsey, Merry L (2018) Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. Transl Res 191:15-28
Lindsey, Merry L; Gray, Gillian A; Wood, Susan K et al. (2018) Statistical considerations in reporting cardiovascular research. Am J Physiol Heart Circ Physiol 315:H303-H313
Mouton, Alan J; DeLeon-Pennell, Kristine Y; Rivera Gonzalez, Osvaldo J et al. (2018) Mapping macrophage polarization over the myocardial infarction time continuum. Basic Res Cardiol 113:26
Lindsey, Merry L; Jung, Mira; Yabluchanskiy, Andriy et al. (2018) Exogenous CXCL4 Infusion Inhibits Macrophage Phagocytosis by Limiting CD36 Signaling to Enhance Post-myocardial Infarction Cardiac Dilation and Mortality. Cardiovasc Res :
Lindsey, Merry L (2018) Reg-ulating macrophage infiltration to alter wound healing following myocardial infarction. Cardiovasc Res 114:1571-1572
DeLeon-Pennell, Kristine Y; Mouton, Alan J; Ero, Osasere K et al. (2018) LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling. Basic Res Cardiol 113:40

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