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Effects of insulin and free fatty acids on matrix metalloproteinases

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Abstract

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 [TIMPs]) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping. Hyperinsulinemia increased the active forms of MMP-2 (∼ sixfold), MMP-9 (∼ 13-fold), and membrane type 1-MMP (MT1-MMP; ∼ 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 ∼ six-to ∼ 11-fold), MMP-9 (from ∼ 13-to ∼ 23-fold), MT1-MMP (from ∼ eight-to ∼ 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.

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References and Recommended Reading

  1. Reaven GM: The role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607.

    Article  PubMed  CAS  Google Scholar 

  2. Hennekens CH: Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation 1998, 97:1095–1102.

    PubMed  CAS  Google Scholar 

  3. Newby AC: Dual role of matrix metalloproteinases (matrixins) in intimal thickening of atherosclerotic plaque rupture. Physiol Rev 2005, 85:1–31.

    Article  PubMed  CAS  Google Scholar 

  4. Bendeck MP, Zempo N, Clowes AW, et al.: Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 1994, 75:539–545.

    PubMed  CAS  Google Scholar 

  5. Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994, 94:2493–2503.

    Article  PubMed  CAS  Google Scholar 

  6. Pasterkamp G, Schoneveld AH, Hijnen DJ, et al.: Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteinases 1, 2 and 9 in the human coronary artery. Atherosclerosis 2000, 150:245–253.

    Article  PubMed  CAS  Google Scholar 

  7. Goodall S, Porter KE, Bell PR, Thompson MM: Enhanced invasive properties exhibited by smooth muscle cells are associated with elevated production of MMP-2 in patients with aortic aneurysms. Eur J Vasc Endovasc Surg 2002, 24:72–80.

    Article  PubMed  CAS  Google Scholar 

  8. Longo GM, Xiong W, Greiner TC, et al.: Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002, 110:625–632.

    PubMed  CAS  Google Scholar 

  9. Blankenberg S, Rupprecht HJ, Poirier O, et al.: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003, 107:1579–1585.

    Article  PubMed  CAS  Google Scholar 

  10. Tataranni PA, Ortega E: A burning question: does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes? Diabetes 2005, 54:917–927.

    Article  PubMed  CAS  Google Scholar 

  11. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases. Structure, function and biochemistry. Circ Res 2003, 92:827–839.

    Article  PubMed  CAS  Google Scholar 

  12. Reaven GM, Hollenbeck C, Jenk CY, et al.: Measurement of plasma glucose, free fatty acid, lactate and insulin for 24 h in patients with NIDDM. Diabetes 1998, 37:1020–1024.

    Article  Google Scholar 

  13. Boden G, She P, Mozzoli M, et al.: Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 2005, 54:3458–3465.

    Article  PubMed  CAS  Google Scholar 

  14. Boden G: Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997, 46:3–10.

    Article  PubMed  CAS  Google Scholar 

  15. Saltiel RA, Kahn CR: Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001, 414:799–806.

    Article  PubMed  CAS  Google Scholar 

  16. Seger R, Krebs EG: The MAPK signaling cascade. FASEB J 1995, 9:726–735.

    PubMed  CAS  Google Scholar 

  17. Jiang ZY, Lin YW, Clemont A, et al.: Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999, 104:447–457.

    Article  PubMed  CAS  Google Scholar 

  18. Cusi K, Maezono K, Osman A, et al.: Insulin resistance differentially affects the PI 3-kinase-and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000, 105:11–20.

    Article  Google Scholar 

  19. Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulin resistance. Nature 2002, 420:333–336.

    Article  PubMed  CAS  Google Scholar 

  20. Miller BS, Shankavaram UT, Horney MJ, et al.: Activation of cJun NH2-terminal kinase/stress-activated protein kinase by insulin. Biochem 1996, 35:8769–8775.

    Article  CAS  Google Scholar 

  21. Malhi H, Bronk SF, Werneburg NW, Gores GJ: Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 2006, 281:12093–12101.

    Article  PubMed  CAS  Google Scholar 

  22. Gao Z, Zhang X, Zuberi A, et al.: Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol 2004, 18:2024–2034.

    Article  PubMed  CAS  Google Scholar 

  23. Ozcan U, Cao Q, Yilmaz E, et al.: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306:457–461.

    Article  PubMed  Google Scholar 

  24. Cuenda A, Cohen P, Buee-Scherrer V, Goedert M: Activation of stress-activated kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6): comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J 1997, 16:295–305.

    Article  PubMed  CAS  Google Scholar 

  25. Collins QF, Xiong Y, Lupo EG, et al.: p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. J Biol Chem 2006, 281:24336–24344.

    Article  PubMed  CAS  Google Scholar 

  26. Raingeaud J, Gupta S, Rogers JS, et al.: Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995, 270:7420–7426.

    Article  PubMed  CAS  Google Scholar 

  27. Miller TA, LeBrasseur NK, Cote GM, et al.: Oleate prevents palmitate-induced cytotoxic stress in cardiac myocytes. Biochem Biophys Res Commun 2005, 336:309–315.

    Article  PubMed  CAS  Google Scholar 

  28. Dersch K, Ichijo J, Bhakdi S, Husmann M: Fatty acids liberated from low-density lipoprotein trigger endothelial apoptosis via mitogen-activated protein kinases. Cell Death Differ 2005, 12:1107–1114.

    Article  PubMed  CAS  Google Scholar 

  29. Zarubin T, Han J: Activation and signaling of the p38 MAP kinase pathway. Cell Res 2005, 15:11–18.

    Article  PubMed  CAS  Google Scholar 

  30. Boden G, Song W, Pashko L, Kresge K: In vivo effects of insulin and free fatty acids on matrix metalloproteinases in rat aorta. Diabetes 2008, 57:476–483.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Temple University Hospital, 3401 North Broad Street, Philadelphia, PA, 19140, USA

    Guenther Boden

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  1. Guenther Boden
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  2. Wei Wei Song
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Correspondence to Guenther Boden.

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Boden, G., Song, W.W. Effects of insulin and free fatty acids on matrix metalloproteinases. Curr Diab Rep 8, 239–242 (2008). https://doi.org/10.1007/s11892-008-0041-y

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  • DOI: https://doi.org/10.1007/s11892-008-0041-y

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