Premium
An Elevated Fibrinogen Increases Matrix Metalloproteinases Activity in Cardiac Microvascular Endothelial Cells
Author(s) -
Patibandla Phani Kumar,
Tyagi Neetu,
Tyagi Suresh C.,
Dean William L.,
Roberts Andrew M.,
Lominadze David
Publication year - 2009
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.23.1_supplement.592.10
Subject(s) - matrix metalloproteinase , endocrinology , mmp9 , chemistry , medicine , endothelial stem cell , fibrinogen , endothelium , biochemistry , in vitro , downregulation and upregulation , gene
Cardiovascular diseases such as hypertension, diabetes, and stroke are accompanied by increased blood fibrinogen (Fg) content. Increased levels of Fg is considered to be a high cardiovascular risk factor. We previously showed that elevated concentration Fg causes arteriolar constriction through release of endothelin‐1 (AJP, 2005; 288: H1257‐H1264) and increases endothelial cell (EC) layer permeability through formation of filamentous actin (Mol. Cell. Biochem, 2008; 307: 13‐22). To further investigate the mechanisms of Fg effects on microvascular permeability, we tested the hypothesis that Fg may be involved in vascular remodeling by activating matrix metaloproteinases (MMPs). Rat cardiac microvascular endothelial cell (RMVEC) cultures were treated with one of the following for 24 h: Fg (2 or 4 mg/ml), Fg (4 mg/ml) with MMP inhibitor GM6001 (1 μM), or medium (control). Activation of MMPs in the subendothelial matrix after addition of MMP substrate was assessed by measuring fluorescence intensity of the medium using a fluorometer. Activation of MMP9 was determined by an MMP9‐specific ELISA kit. Fg caused a dose‐dependent increase in activation of MMPs in the medium (97 ± 6 and 137 ± 12 fluorescence intensity units, FIU with 2 and 4 mg/ml Fg respectively, vs. 82 ± 6 FIU for control, mean±SE). Formation of active MMP9 was increased by 4 mg/ml of Fg (0.054 ± 0.001 ng/ml vs. 0.034 ± 0.004 ng/ml for control). Activation of MMPs by this dose of Fg was inhibited by GM6001, a nonspecific MMP inhibitor. These data suggest that an increased level of Fg induces activation of MMPs, and thus, may be a mechanism for the Fg‐induced increased EC layer permeability seen earlier. Supported by NIH grant # HL080394 to DL.