Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition.
BACKGROUND
A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs.


RESULTS
LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors.


CONCLUSIONS
This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.
Chapman
R English
RE
Cardiothoracic Surgery Research, Medical University of South Carolina, 114 Doughty Street, Strom Thurmond Research Building, Room 625, Charleston, SC 29403, USA.
Scott
Amelia A
AA
Deschamps
Anne M
AM
Lowry
Abigail S
AS
Stroud
Robert E
RE
Ikonomidis
John S
JS
Spinale
Francis G
FG
D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000276:immunology / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D061965:Matrix Metalloproteinase Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases