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Matrix metalloproteinase‐12 inhibition causes cardiac dysfunction post‐myocardial infarction in mice (1151.3)
Author(s) -
Iyer Rugmani,
Patterson Nicolle,
Dive Vincent,
Lindsey Merry
Publication year - 2014
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.28.1_supplement.1151.3
Subject(s) - saline , cd44 , matrix metalloproteinase , myocardial infarction , medicine , ejection fraction , apoptosis , cardiac function curve , extracellular matrix , endocrinology , ligation , cardiology , chemistry , cell , heart failure , biochemistry
Matrix Metalloproteinases ‐12 (MMP‐12) deficiency diminishes the capacity to degrade extracellular matrix, but whether MMP‐12 inhibition post‐myocardial infarction (MI) is an effective therapeutic strategy has not been studied. Male C57BL/6J mice (3‐6 months old, n=60) were subjected to left coronary artery ligation. Saline or MMP‐12 inhibitor (MMP‐12i; 0.5 mg/kg/day) were delivered 3h post‐MI, and the mice were sacrificed at days 0 (no MI), 1 and 7 post‐MI. Infarct area was similar in the saline and MMP‐12i (p=0.70) groups, indicating similar initial injury. Survival rates were 33% for saline and 50% for the MMP‐12i (p=0.29). MMP‐12i group had 33±1% reduction in MMP‐12 activity at d1 post‐MI compared to the saline group (p<0.05). MMP‐12 inhibition worsened LV function at d7 post‐MI, as shown by larger LV volumes and decreased ejection fraction (all p<0.05). CD44, a cell adhesion molecule was 50±1% lower in RNA and protein levels in MMP12i group (both p<0.05). Hyaluronan (HA), a ligand of CD44, had reduced clearance at d1 and d7 post‐MI in MMP12i group. Accumulated HA increased levels of an apoptosis marker, caspase 3 at d7 post‐MI in the MMP12i group. Overexpression of caspase 3 leads to attenuated cardiac function post‐MI. In conclusion, MMP‐12 inhibition post‐MI reduced CD44‐HA interaction leading to increased apoptosis which resulted in LV dysfunction. Grant Funding Source : Supported by HHSN268201000036C, HL051971, R01 HL‐075360, 5I01BX000505