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Published on: April 17, 2021
Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying
Rugmani Padmanabhan Iyer1, Nicolle L Patterson2, Fouad A Zouein1
1San 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.
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.
Insights
Matrix metalloproteinase-12 (MMP-12) plays a protective role post-myocardial infarction by promoting neutrophil apoptosis. Inhibiting MMP-12 worsens left ventricular function by prolonging inflammation.
Area of Science:
- Cardiovascular Biology
- Enzymology
- Immunology
Background:
- Matrix metalloproteinases (MMPs) are crucial in regulating left ventricular (LV) remodeling after myocardial infarction (MI).
- MMP-12 is known for its role in atherosclerotic plaque remodeling, but its specific functions post-MI were unexamined.
- This study investigates the novel post-MI roles of MMP-12.
Purpose of the Study:
- To elucidate the mechanisms of MMP-12 activity in the context of myocardial infarction.
- To determine the cellular sources and functional consequences of MMP-12 expression post-MI.
- To evaluate the therapeutic potential of MMP-12 inhibition in a mouse model of MI.
Main Methods:
- Male C57BL/6J mice underwent left coronary artery ligation to induce MI.
- Mice received either saline or an MMP-12 inhibitor (RXP 470.1) starting 3 hours post-MI.
- Mice were analyzed at various time points (day 1, 3, 5, 7) post-MI, with comparisons to non-MI controls.
Main Results:
- MMP-12 expression increased early post-MI, with neutrophils identified as a surprising cellular source.
- MMP-12 inhibition led to increased LV dilation and worsened LV function, despite similar infarct sizes and survival rates.
- Inhibition of MMP-12 impaired CD44-hyaluronan interactions, reduced neutrophil apoptosis, and prolonged pro-inflammatory cytokine upregulation.
Conclusions:
- MMP-12 exhibits a novel protective function in neutrophil biology post-MI.
- MMP-12 inhibition disrupts CD44-hyaluronan interactions, suppressing neutrophil apoptosis and exacerbating inflammation.
- These findings highlight MMP-12 as a potential therapeutic target for improving cardiac function after MI.
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