Insulin signaling in the arterial wall

doi:10.1016/S0002-9149(99)00353-7

The American Journal of Cardiology

Volume 84, Issue 1, Supplement 1, 8 July 1999, Pages 21-24

https://doi.org/10.1016/S0002-9149(99)00353-7 Get rights and content

Abstract

Insulin has several direct vascular actions that contribute to either vascular protection or injury, depending on the cell type. Vascular protective effects of insulin include stimulation of endothelial cell production of the vasodilator nitric oxide (NO). This, in turn, inhibits formation of lesions dependent on migration and proliferation of vascular smooth muscle cells (VSMCs), attenuates binding of inflammatory cells to the vascular wall, and inhibits thrombosis by reducing platelet adhesion and aggregation. However, insulin also promotes a host of deleterious vascular effects by stimulating the actions of various growth factors acting through the mitogen-activated protein kinase (MAPK) signaling pathway. MAPK may mediate the effects of insulin and angiotensin II on VSMC production of plasminogen activator inhibitor-1, which attenuates fibrinolysis. Thus, 1 of the 2 major pathways of insulin action is the phosphatidylinositol 3-kinase pathway, which is important for glucose transport in skeletal muscle, as well as endothelial NO production and insulin-induced vasodilation. The second insulin-activated pathway is the MAPK pathway, which promotes VSMC growth factors and migration induced by insulin, thrombin, angiotensin II, and platelet-derived growth factor. The thiazolidinediones, which act as ligands for peroxisomal proliferator–activated receptor γ, may inhibit VSMC growth and migration through inhibition of a variety of transcription factors involved in the MAPK pathway.

Section snippets

Tissue effects of insulin

In vitro studies of vascular tissue show that insulin has direct actions that contribute to either vascular protection or injury, depending on cell type.

Pathways of insulin action

When insulin activates its receptors, 2 major pathways are turned on (Figure 1). The first is the phosphatidylinositol 3-kinase pathway, which is important for glucose transport in skeletal muscle. More recently, this pathway has been shown to be important for endothelial nitric oxide production and leads to insulin-induced vasodilation. If nitric oxide production is inhibited with N-monomethyl-l-arginine (L-NMMA), the vasodilatory effects of nitric oxide are also inhibited. The second

Role of insulin sensitizers in insulin resistance

The thiazolidinediones are insulin-sensitizing agents that have helped us to better understand the benefits of improving insulin resistance. How these agents increase insulin-mediated glucose uptake is unclear. They appear to act as a ligand for a nuclear receptor, the peroxisomal proliferator–activated receptor γ (PPARγ),30 augmenting insulin action by enhancing insulin signaling at a postreceptor step. The effects of these agents in skeletal muscle may be direct or indirect. Troglitazone, the

Three components to migration

Our laboratory has been studying the processes involved in migration of a cell (unpublished data). There appear to be 3 components to migration.

Conclusion

Various growth factors (e.g., insulin, angiotensin II, basic fibroblast growth factor, and platelet-derived growth factor) can act through a common signaling pathway—the MAPK pathway—in the vasculature. MAPK mediates growth and migration. It also mediates plasminogen activator inhibitor-1 expression. These growth factors tend to enhance PPARγ expression in VSMCs. If these ligands are activated early, the effects of the MAPK pathway are inhibited—not necessarily through inhibition of MAPK

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Citation Excerpt :
Defective activation of the PI3K/AKT pathway during insulin resistance impairs NO production, while the MAPK pathway is excessively activated by the compensatory hyperinsulinemia and exogenous insulin administration. The activation of the MAPK pathway by insulin encourages the migration and proliferation of VSMCs and collagen synthesis, which are critical steps for the progression of atherosclerotic lesions (Cersosimo, Xu, & Musi, 2012; Coletta et al., 2008; Hsueh & Law, 1999). Moreover, insulin not only enhances LDL synthesis in adipose tissue, but also increases cholesterol transport into artery walls by altering expression of the LDL receptor (Borggreve, De Vries, & Dullaart, 2003; Stout, 1990).
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Original ArticlesInsulin signaling in the arterial wall

Abstract

Section snippets

Tissue effects of insulin

Pathways of insulin action

Role of insulin sensitizers in insulin resistance

Three components to migration

Conclusion

J Biol Chem

FEBS Lett

Kidney Int

Exp Cell Res

FEBS Lett

Am J Med

Endothelium in insulin resistance and diabetes

Diabetes Rev

Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasiaa serial intravascular ultrasound study

Circulation

The intimasoil for atherosclerosis and restenosis

Circ Res

The pathogenesis of coronary artery disease and the acute coronary syndromes

N Engl J Med

Atherosclerotic plaque ruptureemerging insights and opportunities

Am J Cardiol

Vascular reactivity

Am J Cardiol

Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells

J Clin Invest

Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells

Circ Res

Gene therapy inhibiting neointimal vascular lesionin vivo transfer of endothelial cell nitric oxide synthase gene

Proc Natl Acad Sci USA

Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide

J Clin Invest

Nitric oxide decreases cytokine-induced endothelial activationNitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines

J Clin Invest

Original Articles
Insulin signaling in the arterial wall