Myocardial infarction (MI), even with current reperfusion strategies, remains the leading cause of heart failure. The identification of events that stimulate adverse remodeling of the left ventricle (LV) post-MI, therefore, will provide therapeutic targets to prevent, slow, or reverse the progression to heart failure. A major risk factor for a poor response to MI is age. We have observed that cardiac aging, in the absence of pathology, induces macrophage infiltration into the left ventricle (LV), increases matrix metalloproteinase-9 (MMP-9) levels in the plasma and the LV, decreases fibroblast function, alters LV structure, and diminishes LV function. Post-MI, extracellular matrix (ECM) remodeling is a driving event, and intial analysis of matrix metalloproteinase-9 (MMP-9) functions in remodeling suggest that this particular MMP predominantly influences extracellular signaling, ECM protein turnover, and fibroblast functions. MMP-9, therefore, is potentially relevant in both the pre- and post-MI settings. The goal of this project, accordingly, is to understand the role of aging on ECM, fibroblast, and macrophage responses to MI. This proposal will focus on elucidating unique MMP-9 driven mechanisms to critically test the hypothesis is that aging induces a baseline increase in MMP-9 and ECM levels, which alters ECM, fibroblast, and macrophage responses to MI. Using wild type and MMP-9 null mice, we will determine which MMP-9 mediated events most influence LV remodeling. To test our hypothesis, we will determine how ECM patterns (aim 1), fibroblast function (aim 2), and macrophage phenotypes (aim 3) regulate the MI response. This proposal is unique because most studies use MMP-9 as an output measurement and only determine whether levels change in response to a stimulus, not how the enzyme regulates ECM remodeling. Our multi-faceted approach includes in vivo physiology, cell biology, biochemistry, proteomic, and histological approaches to further advance the mechanistic understanding of the origins of post-MI LV remodeling and provide targets for translational research. The results of these studies will clarify the consequences of aging on post-MI remodeling.

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 aging influences scar formation by regulating the extracellular matrix environment and two cell types, the fibroblast and macrophage.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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G V Sonny Montgomery VA Medical Center
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DeLeon-Pennell, Kristine Y; Iyer, Rugmani Padmanabhan; Ma, Yonggang et al. (2018) The Mouse Heart Attack Research Tool 1.0 database. Am J Physiol Heart Circ Physiol 315:H522-H530
Bloksgaard, Maria; Lindsey, Merry L; Martinez-Lemus, Luis A (2018) Extracellular Matrix in Cardiovascular Pathophysiology. Am J Physiol Heart Circ Physiol :
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

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