Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase
Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mechanisms are poorly understood. We tested the hypothesis that insulin increases monocyte-endothelial interactions, which are implicated in atherosclerosis.
We treated human umbilical vein endothelial cells with insulin (10−10 to 10−7 mol/l) for 0 to 24 h. To dissect potentially implicated signal transduction pathways, we treated endothelial cells with known pharmacological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3′-kinase (PI3′-kinase) inhibitor wortmannin (3×10−8 to 10−6 mol/l), involved in insulin-induced endothelial nitric oxide synthase stimulation, and the p38 mitogen-activated protein (p38MAP) kinase inhibitor SB-203580 (10−7 to 2×10−6 mol/l). We measured adhesion molecule expression by cell surface enzyme immunoassays and U937 monocytoid cell adhesion in rotational adhesion assays.
At pathophysiological concentrations (10−9 to 10−7 mol/l), insulin concentration-dependently induced vascular cell adhesion molecule (VCAM)-1 (average increase: 1.8-fold) peaking at 16 h. By contrast, the expression of intercellular adhesion molecule-1 and E-selectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the absence of cytotoxicity, wortmannin significantly potentiated the effect of insulin alone on VCAM-1 surface expression and monocytoid cell adhesion, whereas SB-203580 (10−6 mol/l) completely abolished such effects.
These observations indicate that insulin promotes VCAM-1 expression in endothelial cells through a p38MAP-kinase pathway, amplified by the PI3′-kinase blockage. This could contribute to explaining the increased atherosclerosis occurring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3′-kinase pathway.
- Despres JP, Lamarche B, Mauriege P et al. (1996) Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952–957
- Cusi K, Maezono K, Osman A et al. (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105:311–320
- Kuboki K, Jiang ZY, Takahara N et al. (2000) Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 101:676–681
- De Caterina R, Libby P, Peng HB et al. (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–68
- Cybulsky MI, Iiyaa K, Li H (2001) A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 107:1255–1262
- Basta G, Lazzerini G, Massaro M et al. (2002) Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation 105:816–822 CrossRef
- The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 7:1183–1197
- Montagnani M, Golovchenko I, Kim I et al. (2002) Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 277:1794–1799 CrossRef
- Cominacini L, Garbin U, Fratta Pasini A, Lo Cascio V (1996) Increased levels of plasma ELAM-1, ICAM-1 and VCAM-1 in NIDDM: possible role of oxidized LDL. Diabetologia 39:1244
- De Mattia G, Bravi MC, Costanzo A et al. (1999) Effects of insulin on in vitro vascular cell adhesion molecule-1 expression and in vivo soluble VCAM-1 release. Diabetologia 42:1235–1239 CrossRef
- Iida KT, Shimano H, Kawakami Y et al. (2001) Insulin up-regulates tumor necrosis factor alpha production in macrophages through an extracellular-regulated kinase-dependent pathway. J Biol Chem 276:32531–32537 CrossRef
- Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase
Volume 47, Issue 3 , pp 532-536
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- adhesion molecules
- endothelial cells
- Industry Sectors
- Author Affiliations
- 1. Center of Excellence on Aging, Chair of Cardiology, G. d’Annunzio University—Chieti, Ospedale S. Camillo de Lellis, Via Forlanini, 50, 66100, Chieti, Italy
- 2. Center of Excellence on Aging, Chair of Biology, G. d’Annunzio University, Chieti, Italy
- 4. CNR Institute of Clinical Physiology, Pisa and Lecce, Italy
- 3. Center of Excellence on Aging, Chair of Endocrinology and Metabolism, G. d’Annunzio University, Chieti, Italy