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Matrix Metalloproteinase‐12 Reduces Cardiac Dilation Post‐Myocardial Infarction by Decreasing Neutrophil Accumulation
Author(s) -
Iyer Rugmani Padmanabhan,
Castro Brás Lisandra E,
Jung Mira,
Ma Yonggang,
DeLeonPennell Kristine Y,
Flynn Elizabeth R,
Can Presley L,
Cates Courtney A,
Lindsey Merry L
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1210.5
Subject(s) - saline , myocardial infarction , matrix metalloproteinase , medicine , chemistry , apoptosis , ligation , cardiology , immunology , biochemistry
Early inhibition of matrix metalloproteinase‐12 (MMP‐12) worsens cardiac remodeling post‐myocardial infarction (MI), suggesting a beneficial role for MMP‐12. This study assessed whether exogenous MMP‐12 delivery early post‐MI is an effective therapeutic approach. Male C57BL/6J mice (3–6 months old, n=3/group) were subjected to left coronary artery ligation. Saline or active MMP‐12 (aMMP‐12; 0.5mg/kg/day) infusion was initiated at 3h post‐MI using an osmotic mini‐pump. Mice were sacrificed at day (d) 1 or 5 post‐MI. D0 (no MI) served as a negative control. Infarct areas were similar among saline and aMMP‐12 groups at both d1 and d5 (p=0.76 by ANOVA), indicating similar ischemic injury. Survival rates were not significantly different (p=0.38 at d1, p=0.45 at d5). End diastolic volume (EDV) increased in the saline group, and this increase was attenuated in aMMP‐12 (d0= 45±1 μl, saline= 117±4 μl, aMMP‐12= 85±4 μl). At d1 post‐MI, 12 pro‐inflammatory genes were reduced in the aMMP‐12 group (all p<0.05 vs. saline), including Il8rb, Il‐18, Tgf‐β1, and Tnf. Consistent with cytokine levels, neutrophils were reduced in the aMMP‐12 group by 60% at d1 and by 130% at d5 post‐MI (both p<0.05 vs respective saline groups). Neutrophil removal occurs mainly via apoptosis, and we observed a 4‐fold increase in cleaved caspase‐3 in the aMMP‐12 group at d1 and a 2‐fold increase at d5 post‐MI, compared to respective saline groups (all p<0.05). Our results revealed that MMP‐12 plays a cardioprotective role early post‐MI by attenuating neutrophil infiltration and enhancing neutrophil removal to reduce inflammation and LV dilation. Support or Funding Information This work was supported by the American Heart Association 14POST18770012, 14SDG18860050 and 15SDG22930009, the National Institutes of Health 1R03EB009496, SC2HL101430, HHSN 268201000036C (N01‐HV‐00244), HL075360, P01HL051971, P20GM104357, and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award 5I01BX000505