Myocardial infarction (MI), even with current reperfusion strategies, remains the leading cause of heart failure. Identifying the events that induce adverse cardiac remodeling post-MI will provide therapeutic targets to prevent, slow, or reverse progression to heart failure. A major risk factor for a poor response to MI is age. With age, there is an increased infiltration of macrophages into the left ventricle (LV), which stimulates extracellular matrix (ECM) accumulation and leads to a subtle but significant change in LV function evidenced by reduced early (E) to late (A) filling ratios. Post-MI, macrophage infiltration and ECM accumulation are driving events, and matrix metalloproteinase (MMP)-9 regulates both of these processes. MMP-9 deletion attenuates the cardiac response to aging, in part by shifting macrophage polarization from a pro-inflammatory M1 state to an anti- inflammatory M2 state. Our preliminary data demonstrate that MMP-9 levels are much increased in older mice at day 7 post-MI, and this in-crease in MMP-9 yields more M1 macrophages to extend the inflammatory response and delay the healing phase. MMP-9 deletion restores the M1 and M2 polarization balance. This renewal proposal will address the central hypothesis that during the MI response in aging mice, MMP-9 enhances pro-inflammatory M1 polarization and attenuates anti- inflammatory M2 polarization to induce adverse remodeling. To test our hypothesis, we will determine macrophage polarization kinetics in young (3-6 month old) and old (18-23 month old) wild type and MMP-9 null mice. We will evaluate how MMP-9 activates macrophage polarization and how this process is altered with aging (aim 1), whether young hearts can be switched to an old phenotype by stimulating M1 macrophage polarization (aim 2), and whether old hearts can be switched to a young phenotype by stimulating M2 macrophage polarization (aim 3). This proposal is unique, because most studies use MMP-9 as an output measurement whereby we will use MMP-9 as a major input. Our multi-faceted approach includes in vivo physiology, cell biology, biochemistry, proteomics, 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 have high significance for the aging veteran population.
Heart failure is the inability of the heart to pump adequately to supply the body with sufficient oxygen to meet its needs, and heart failure is a leading cause of death in the United States, the veteran population included. Of the 50,000 individuals diagnosed with heart failure each year, 70% of these patients 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 wound healing response, particularly the inflammatory component.
| 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 |
| Lindsey, Merry L; Kassiri, Zamaneh; Virag, Jitka A I et al. (2018) Guidelines for measuring cardiac physiology in mice. Am J Physiol Heart Circ Physiol 314:H733-H752 |
| Lindsey, Merry L; Jung, Mira; Hall, Michael E et al. (2018) Proteomic analysis of the cardiac extracellular matrix: clinical research applications. Expert Rev Proteomics 15:105-112 |
| Mouton, Alan J; Rivera Gonzalez, Osvaldo J; Kaminski, Amanda R et al. (2018) Matrix metalloproteinase-12 as an endogenous resolution promoting factor following myocardial infarction. Pharmacol Res 137:252-258 |
| 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 |
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