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In‐vivo Evidence of C‐Reactive Protein‐Mediated Metalloproteinase‐9 Induction from Rat Macrophages: Molecular Insights
Author(s) -
singh uma,
Devaraj sridevi,
Dasu Mohan R,
Afify A,
Jialal Ishwarlal
Publication year - 2008
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.22.1_supplement.903.4
Subject(s) - zymography , matrix metalloproteinase , in vivo , p38 mitogen activated protein kinases , medicine , blot , in vitro , kinase , mapk/erk pathway , chemistry , endocrinology , biochemistry , biology , microbiology and biotechnology , gene
C‐reactive protein (CRP) present in higher amounts in the atherosclerotic plaques of acute coronary syndrome (ACS) patients colocalizes with macrophages. Matrix metalloproteinases (MMPs) are known to destabilize atherosclerotic plaques with a causal role of MMP‐9 in the disease. MMP‐9 and CRP correlate strongly in ACS patients. Macrophages are the major source of MMP‐9. A paucity of data exists examining the effect of CRP on MMPs in‐vivo. We examined CRP's effect on MMP‐9 activity in rats. Human (hCRP‐test) and human serum albumin (hSA‐control) injected intraperitoneally (20mg/kg b.w/3 days) led to circulating hCRP levels ∼18 mg/L in test group. Zymography revealed significantly increased MMP‐9 activity in peritoneal macrophages of hCRP rats. To elucidate mechanistic insights, hCRP/hSA (25ug/ml) was injected in the pouches formed by injecting 20 ml sterile air on the backs of rats. Zymography/western blotting (MMP‐9 activity/mass) of pouch exudates revealed increased MMP‐9 which was abrogated by injecting inhibitors to p38 MAP kinase, ERK and NFkB, but not JNK prior to hCRP injection. Further, MMP‐9 is reported to have a NFkB element in its promoter. p65 NFkB activity measured in nuclear fractions of macrophages was significantly increased in hCRP rats. To conclude, NFkB is an upstream event in CRP‐mediated MMP‐9 induction. This study presents an in‐vivo evidence of potential role of CRP in plaque instability.