This is an A2 resubmission of a renewal application to study left ventricular remodeling following myocardial infarction (MI). MI, even with current therapeutic strategies, remains a leading cause of heart failure. The identification of events that stimulate adverse remodeling of the left ventricle (LV) post-MI may provide therapeutic targets to prevent, slow, or reverse the progression to heart failure. Post-MI, extracellular matrix (ECM) turnover is a driving event in LV remodeling, and there is a well- established association between the inflammatory response and ECM turnover. An initial analysis of matrix metalloproteinase-9 (MMP-9) functions suggests that this particular MMP predominantly influences remodeling by altering the macrophage response, as MMP-9 null mice show impaired macrophage influx into the LV post- MI. MMP-9 has been shown to cleave ECM to generate bioactive peptides and to activate transforming growth factor b (TGFb), which potentially places MMP-9 downstream of the macrophage and upstream of key events that involve the cardiac fibroblast. The long-term goals of this project, accordingly, are to understand the roles of macrophages and macrophage-derived MMP-9 in the LV response to MI. This proposal will focus on elucidating macrophage and MMP-9 driven mechanisms to critically test the hypothesis that macrophages modulate the LV response to MI through MMP-9 effects on ECM substrates and transforming growth factor-b. Using a unique cell specific transgenic mouse model that overexpresses human MMP-9 only in macrophages and specific MMP-9 and TGFb interventions, we will determine the MMP-9 mediated events that most influence LV remodeling. To test our central hypothesis, we will 1) determine whether macrophage levels and activation status regulate fibroblast activation and LV remodeling;2) determine whether MMP-9 and TGFb regulate macrophage phenotype, fibroblast activation, and LV remodeling;and 3) determine whether bioactive ECM peptides generated by MMP-9 regulate LV remodeling post-MI through macrophage and fibroblast activation. We will use a multi-discipline approach that integrates physiology, cell biology, biochemistry, mass spectrometry, and histological approaches to unveil mechanisms and quantify the LV remodeling process as a function of macrophage activation status and MMP-9 levels. This proposal is innovative because most studies use MMP-9 as an output measurement and only determine whether MMP-9 levels change in response to a stimulus, not how the enzyme regulates ECM remodeling. The results of these studies will clarify the consequences of macrophage-derived MMP-9 on post- MI remodeling. Our multi-faceted approach will further advance the mechanistic understanding of the events that initiate post-MI LV remodeling, which may provide targets for translational research.

Public Health Relevance

Heart failure is the inability of the heart to adequately supply the body with oxygen and is a leading cause of death in the United States. Of the 50,000 heart failure patients diagnosed each year, 70% have heart failure due to a previous heart attack (myocardial infarction;MI). The main objective of this grant is to use a mouse MI model to understand how the macrophage, an inflammatory cell that regulates wound healing, and matrix metalloproteinase-9, an enzyme in the macrophage that regulates scar formation, direct the response to MI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075360-09
Application #
8256754
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2003-12-01
Project End
2013-01-13
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$416,175
Indirect Cost
$125,387
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
Lindsey, Merry L (2018) Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling. Nat Rev Cardiol 15:471-479
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

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