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In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta

From the Division Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Guenther Boden, MD, Temple University Hospital, 3401 North Broad St., Philadelphia, PA 19140. E-mail: bodengh{at}tuhs.temple.edu

Abbreviations: ASVD, atherosclerotic vascular disease; ERK-1/2, extracellular signal–regulated kinase 1/2; FFA, free fatty acid; GIR, glucose infusion rate; IKK, inhibitor of B kinase; JNK, c-jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; MT1-MMP, membrane type 1-MMP; PKC, protein kinase C; PI3K, PI 3-kinase; TBS, Tris-buffered saline; TIMP, tissue inhibitor of MMP

OBJECTIVE—Obesity is associated with insulin resistance, hyperinsulinemia, elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic vascular disease (ASVD). A part of this increased risk may be due to enhanced activation of matrix metalloproteinases (MMPs). Here, we have examined the effects of physiologically elevated levels of insulin and FFA on three MMPs and their inhibitors (tissue inhibitors of MMP [TIMPs]) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping.

RESEARCH DESIGN AND METHODS—Four-hour euglycemic-hyperinsulinemic clamps with infusion of saline/glycerol, lipid/heparin, or insulin with or without lipid/heparin were performed in alert unrestrained male rats.

RESULTS—Hyperinsulinemia increased MMP-2 (6-fold), MMP-9 (13-fold), membrane type 1-MMP (MT1-MMP; 8-fold) (all Western blots), and gelatinolytic activity (zymography) of MMP-2 (2-fold), while not affecting TIMP-1 and TIMP-2. Insulin increased IRS-1–associated PI 3-kinase (PI3K), extracellular signal–regulated kinases 1/2 (ERK1/2), and c-jun NH₂-terminal kinase (JNK) (by Western blots with phospho-specific antibodies). FFA augmented the insulin-mediated increases in MMP-2 (from 6- to 11-fold), MMP-9 (from 3- to 23-fold), MT1-MMP (from 8- to 20-fold), MMP-2 gelatinolytic activity (from 2- to 3-fold), and JNK and p38 mitogen-activated protein kinase (MAPK) activities but decreased insulin-mediated activation of PI3K and ERK1/2. Raising FFA without raising insulin affected neither MMPs nor TIMPs.

CONCLUSIONS—FFA augmented insulin stimulation of the MMP/TIMP balance of three proatherogenic MMPs and increased activities of two MAPKs (JNK and p38 MAPK), both of which are known to stimulate the production of proinflammatory cytokines. This may, over time, increase degradation of extracellular matrix and together with inflammatory changes promote development of ASVD.

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