Date of Award

1-1-2002

Embargo Period

1-1-2002

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Physiology

Additional Department

Neuroscience

College

College of Graduate Studies

First Advisor

Frank Spinale

Second Advisor

David Perry

Third Advisor

George Tempel

Fourth Advisor

Rupak Mukherjee

Fifth Advisor

John Ikonomidis

Abstract

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, and TIMP-1 release in LVHMFs. Methods and Results: LVHMF cultures were established from five individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 mm) for 12 to 36 hours. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 hours 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 30% from time-matched values following 36 hours 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 human LV myocardial fibroblasts. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.

Rights

All rights reserved. Copyright is held by the author.

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