Rugmani Padmanabhan Iyer1, Nicolle L Patterson2, Fouad A Zouein1, Yonggang Ma1, Vincent Dive3, Lisandra E de Castro Brás4, Merry L Lindsey5. 1. San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA. 2. San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA. 3. Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines Bat, 152, CE-Saclay, Gif-sur-Yvette, France. 4. San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA. 5. San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA. Electronic address: mllindsey@umc.edu.
Abstract
RATIONALE: Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. OBJECTIVE: The goal was to determine MMP-12 post-MI mechanisms. METHODS AND RESULTS: Male C57BL/6J mice (3-6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5mg/kg/day) was delivered by osmotic mini-pump beginning 3h post-MI, and mice were sacrificed at day (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n=6-12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33 ± 1% at d1 post-MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro-inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post-MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP-12 directly stimulated CD44, caspase 3, and caspase 8 expression. CONCLUSION: Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function.
RATIONALE: Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. OBJECTIVE: The goal was to determine MMP-12 post-MI mechanisms. METHODS AND RESULTS: Male C57BL/6J mice (3-6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5mg/kg/day) was delivered by osmotic mini-pump beginning 3h post-MI, and mice were sacrificed at day (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n=6-12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33 ± 1% at d1 post-MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro-inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post-MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP-12 directly stimulated CD44, caspase 3, and caspase 8 expression. CONCLUSION: Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function.
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