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 #
7R01HL075360-10
Application #
8623279
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2003-12-01
Project End
2015-04-30
Budget Start
2013-06-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$366,283
Indirect Cost
$120,178
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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DeLeon-Pennell, Kristine Y; Meschiari, Cesar A; Jung, Mira et al. (2017) Matrix Metalloproteinases in Myocardial Infarction and Heart Failure. Prog Mol Biol Transl Sci 147:75-100
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DeLeon-Pennell, Kristine Y; Iyer, Rugmani Padmanabhan; Ero, Osasere K et al. (2017) Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing. JCI Insight 2:
Iyer, Rugmani Padmanabhan; Jung, Mira; Lindsey, Merry L (2016) MMP-9 signaling in the left ventricle following myocardial infarction. Am J Physiol Heart Circ Physiol 311:H190-8

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