Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution

International Journal of Cardiology
Rugmani Padmanabhan IyerMerry L Lindsey

Abstract

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. The goal was to determine MMP-12 post-MI mechanisms. 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 rem...Continue Reading

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Citations

Jan 8, 2016·Journal of Molecular and Cellular Cardiology·Samantha D Francis StuartCrystal M Ripplinger
Jan 2, 2016·Journal of Molecular and Cellular Cardiology·Merry L LindseyYonggang Ma
Jan 31, 2016·Cardiovascular Research·Yonggang MaMerry L Lindsey
May 29, 2016·Seminars in Cell & Developmental Biology·Emily L Ongstad, Robert G Gourdie
Oct 21, 2016·Bioconjugate Chemistry·Thomas BordenaveLaurent Devel
Oct 20, 2015·Trends in Pharmacological Sciences·Mauro PerrettiTrinidad Montero-Melendez
Oct 18, 2016·Journal of Molecular and Cellular Cardiology·Rugmani Padmanabhan IyerMerry L Lindsey
Dec 6, 2016·Scientific Reports·Mahmoud RazavianMehran M Sadeghi
Jun 22, 2017·Biochimica Et Biophysica Acta. Molecular Cell Research·Maxim LevinIrit Sagi
Jan 20, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Merry L LindseyGerd Heusch
Aug 16, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Rugmani Padmanabhan IyerMerry L Lindsey
Nov 19, 2015·Circulation. Cardiovascular Genetics·Kristine Y DeLeon-PennellMerry L Lindsey
Oct 17, 2017·American Journal of Physiology. Heart and Circulatory Physiology·Cesar A MeschiariMerry L Lindsey
Sep 29, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Laurent DevelIsabelle Texier
Feb 23, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Amanda R KaminskiMerry L Lindsey
Jun 24, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Bochra Tourki, Ganesh Halade
May 19, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Kristine Y DeLeon-PennellMerry L Lindsey
Jun 6, 2018·Basic Research in Cardiology·Alan J MoutonMerry L Lindsey
Dec 30, 2017·Expert Review of Proteomics·Merry L LindseyKristine Y DeLeon-Pennell
Aug 23, 2018·Basic Research in Cardiology·Kristine Y DeLeon-PennellMerry L Lindsey
May 13, 2018·Nature Reviews. Cardiology·Merry L Lindsey
Dec 14, 2018·Basic Research in Cardiology·Mira JungThomas Thum
Jun 17, 2020·The American Journal of the Medical Sciences·Larysa Aleksenko, Isaac K Quaye
Jul 2, 2021·Matrix Biology Plus·Jesse D RogersWilliam J Richardson
May 22, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Kyle T DittloffBrenda Russell
Oct 13, 2020·The American Journal of Emergency Medicine·Lisandra E de Castro BrásWilliam J Meggs
Oct 12, 2019·Journal of Medicinal Chemistry·Jakub ToczekLaurent Devel
Oct 9, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Merry L LindseyZamaneh Kassiri

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