Abstract

Objective: Obesity is associated with insulin resistance, hyperinsulinemia, elevated plasma 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 3 MMPs and their inhibitors (TIMPs) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping.

Methods and Results: Hyperinsulinemia increased MMP-2 (∼ 6-fold), MMP-9 (∼ 13-fold) and membrane type 1-MMP (MT1-MMP, ∼ 8-fold), (all Western blots), the gelatinolytic activity (zymography) of MMP-2 (2-fold), while not affecting TIMP-1 and TIMP-2. Insulin increased IRS-1 associated PI3 kinase (PI3 K), extracellular signal-regulated kinases 1/2 (ERK 1/2) 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), increased JNK and p38 mitogen activated protein kinase (p38 MAPK) activities but decreased insulin mediated activation of PI3 K and ERK 1/2. 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 2 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.