Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

Temporal regulation of MMPs during coronary collateral growth in the metabolic syndrome

Investigator: Luke Wiggins, University of South Alabama College of Medicine

Mentor: Petra Rocic, PhD, Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine

A noninvasive alternative to PTCA or CABG is coronary collateral growth (CCG). Transient, repetitive ischemia (RI) is a natural stimulus for CCG. However, CCG is impaired in the human metabolic syndrome (MS), as well as in the rat model of the metabolic syndrome (JCR). A necessary component of CCG is vascular smooth muscle cell (VSMC) proliferation and migration which must be associated with temporally regulated degradation of the vascular extracellular matrix (ECM). We hypothesized that decreased or temporally altered activation of matrix metalloproteinases (MMPs), which can degrade components of the ECM, correlates with decreased CCG in the JCR rats compared with normal rats (SD). Therefore, we focused on broad specificity MMPs 3 and 7, metalloelastase MMP 12, membrane type MT1-MMP (MMP 14), and collagenases, MMPs 1, 8 and 13. To induce RI, left thoracotomy was performed, and a pneumatic occluder was implanted over the left anterior descending coronary artery (LAD). The RI protocol consisted of: 8 x 40 sec occlusions, every 20 min repeated every 8 hrs for 0, 3, 6, or 9 days. MMP activation was determined by Western blot utilizing the difference in molecular weights of active vs. inactive forms. Of the broad specificity MMPs and the collagenases, only MMP 7 and MMP 8 were activated by RI in either rat phenotype. Activation of MMP 7 was increased (~2 fold) on days 3 and 6 of RI in the SD but not in JCR rats. MMP 8 activation was significantly increased on day 3 of RI in the SD animals (~2 fold). In contrast, its activation was significantly increased on days 6 (~4 fold) and 9 (~3 fold) of RI in the JCR rat. The elastase, MMP 12, was not activated in the SD animals; however, RI resulted in significantly increased activation (~4 fold) of MMP 12 on days 6 and 9 of the RI protocol in the JCR rats. MT1-MMP activation was increased (~1.5 and 2 fold, respectively) in the SD but not the JCR animals on days 3 and 6 of RI. We conclude that RI-induced CCG is associated with temporally tightly controlled activation of specific MMPs. Importantly, compromised CCG in the metabolic syndrome may be partially due to lack of and temporally altered activation of specific MMPs.

Updated on March 22, 2012.

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