Effects of insulin and free fatty acids on matrix metalloproteinases.
To investigate if increased activation of matrix metalloproteinases (MMPs) may contribute to the large cardiovascular risk associated with obesity-related insulin resistance, we examined the effects of physiologically elevated levels of insulin and free fatty acid (FFA) on three MMPs and their physiologic inhibitors (tissue inhibitors of MMP ) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping. Hyperinsulinemia increased the active forms of MMP-2 (approximately sixfold), MMP-9 (approximately 13-fold), and membrane type 1-MMP (MT1-MMP; approximately eightfold) (all Western blots), and the gelatinolytic activity (zymography) of MMP-2 (twofold); it did not affect TIMP-1 and TIMP-2. FFA augmented the insulin-mediated increases in MMP-2 (from approximately six- to approximately 11-fold), MMP-9 (from approximately 13- to approximately 23-fold), MT1-MMP (from approximately eight- to approximately 20-fold), and MMP-2 gelatinolytic activity (from two- to threefold). FFA also increased JNK and p38 mitogen-activated protein kinase activities. The insulin- and FFA-induced hyperactivity of three proatherogenic MMPs in vascular tissues may promote degradation of extracellular matrix over time, leading to thinning of atherosclerotic capsules and acute vascular problems.
Boden
Guenther
G
Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140, USA. bodengh@tuhs.temple.edu
Song
Wei Wei
WW
D000818:Animals; D001011:Aorta / Q000201:enzymology; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000201:enzymology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases