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phosphorylation activity (23,27). The insulin receptor is a member of the tyrosine kinase family, and the activation of the receptor by insulin-binding results in autophosphorylation of receptor and activation of tyrosine kinase (Fig. 1). As in other cells, insulin receptors in vascular cells can activate at least two different signal transduction pathways; one is PI 3-kinase (PI3K) cascades and the other is Ras-mitogen-activated protein (MAP) kinase cascades. These signaling processes mediate the many actions of insulin in vascular cells, such as the regulation of cell growth, gene expression, protein synthesis, and glycogen incorporation. However, insulin receptors can mediate unusual functions in endothelial cells. We have demonstrated that endothelial cells can internalize insulin via a receptor-mediated process and transport the insulin across the endothelial cell without degradation (28,29). In contrast, other types of endothelial cells, such as hepa-tocytes or adipocytes, will heavily degrade insulin when it is internalized. Another vascular-specific action of insulin is the activation or increased expression of nitric oxide (NO), resulting in localized vasodilation (30-33). Mice null for insulin receptor specifically in endothelial cells (VENIRKO mice) were recently established (34). Although only less than 5% of the insulin receptor mRNA expression was left in endothelial cells, these mice develop normally and did not show major differences in their vasculature as compared to their control litter mates except a mild reduction of gene expression for endothelial nitric oxide synthase (eNOS) and endothelin-1 in endothelial cells (34). However, when challenged with hypoxia, VENIRKO mice developed more than 50% reduction in retinal neovascularization (35). These results suggest that the alteration of insulin signaling might affect the expression of vascular regulators in endothelial cells and further affect vascular biology such as neovascularization.

Besides these actions, insulin has been reported to have many biological and physiological actions on vascular cells (Table 2). It is believed that hyperinsulinemia or insulin resistance can contribute to the acceleration of atherosclerosis by increasing the proliferation of aortic smooth muscle cells and the synthesis of extracellular matrix (ECM) proteins in the arterial wall (Fig. 2). However, the mitogenic actions of insulin on cells may not be significant in physiological conditions (36), because insulin can only stimulate the growth of vascular cells at concentrations greater than 10 nmol/L. Only in severe insulin-resistant or hyperinsulinemic state can the plasma level of insulin may exert its growth-promoting actions in smooth muscle cells (SMCs) by enhancing the mitogenic action of more potent growth factors, such as platelet-derived growth factor and insulinlike growth factors (37).

One of the best-characterized vascular effects of insulin is its vasodilatory action, which is mainly mediated by the production of NO (31). Baron (30) reported that blood flow to the leg increased by two fold after 4 hours of hyperinsulinemia during a euglycemic-hyperinsulinemic clamp study. With superimposed infusion of NG-monomethyl-L-arginine (l-NMMA), an inhibitor of NO synthase, into the femoral artery,

Fig. 1. Schematic diagram of the signaling pathways of insulin in vascular endothelial cells. Activation of either PI3K/Akt or Ras/MEK/MAP-kinase pathways can mediate most actions of insulin, with the former stimulating mainly anti-atherogenic effects, whereas the latter stimulating atherogenic actions. In diabetic or insulin-resistant states, metabolic derangements or activation of PKC has been suggested to selectively inhibit Insulin receptor-mediated activation of PI3K/Akt pathway, but spare the Ras/MEK/MAP pro-atherogenic arm of insulin's signaling cascade. This may in turn contribute to atherogenic lesion formation. IRS, insulin-receptor substrate; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen activated protein kinase.

Fig. 1. Schematic diagram of the signaling pathways of insulin in vascular endothelial cells. Activation of either PI3K/Akt or Ras/MEK/MAP-kinase pathways can mediate most actions of insulin, with the former stimulating mainly anti-atherogenic effects, whereas the latter stimulating atherogenic actions. In diabetic or insulin-resistant states, metabolic derangements or activation of PKC has been suggested to selectively inhibit Insulin receptor-mediated activation of PI3K/Akt pathway, but spare the Ras/MEK/MAP pro-atherogenic arm of insulin's signaling cascade. This may in turn contribute to atherogenic lesion formation. IRS, insulin-receptor substrate; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen activated protein kinase.

Table 2

List of Effects of Insulin in Vascular Cells

Glucose incorporation into glycogen

Amino acid transport

Endothelin expression eNOS expression and activation

VEGF expression in vascular smooth muscle cells

Tyrosine phosphorylation of various proteins

Exocytosis and receptor-mediated transcytosis

Basement matrix synthesis

Increased plasminogen activator inhibitor I

c-myc, c-fos expression

Protein synthesis

DNA synthesis

Cellular proliferation the vasodilation was completely abrogated. It has also been reported that insulin-mediated vasodilation is impaired in states of insulin-resistant states (38). Consistent with this observation, obese nondiabetic subjects often have impaired endothelium-dependent vasodilation, especially relative to the patients with type 2 diabetes (32). These findings suggest that endothelial cell dysfunction may have genetic base and is involved in the risk

Fig. 2. Mechanism of DAG synthesis and PKC activation in diabetes mellitus. Hyperglycemia activates the de novo synthesis of DAG and leads to PKC activation. Acy-CoA, aceyl-coenzyme A; CoA, coenzyme A; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; FDP, fructose 1,6-diphosphate; F6P, fructose 6 phosphate; GAP, glyceradehyde 3 phosphate; G3P, glycerol 3 phosphate; G6P, glucose 6 phosphate; IP3, inositol 1,4,5-triphosphate; LysoPA, lysophosphatidic acid; PA, phosphatidic acid; PC, phosphatidylcholine; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PLD, phospholipase D.

Fig. 2. Mechanism of DAG synthesis and PKC activation in diabetes mellitus. Hyperglycemia activates the de novo synthesis of DAG and leads to PKC activation. Acy-CoA, aceyl-coenzyme A; CoA, coenzyme A; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; FDP, fructose 1,6-diphosphate; F6P, fructose 6 phosphate; GAP, glyceradehyde 3 phosphate; G3P, glycerol 3 phosphate; G6P, glucose 6 phosphate; IP3, inositol 1,4,5-triphosphate; LysoPA, lysophosphatidic acid; PA, phosphatidic acid; PC, phosphatidylcholine; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PLD, phospholipase D.

of atherosclerosis in subjects with insulin resistance regardless whether they have diabetes (32).

The effect of insulin on NO production in the endothelial cells may be biphasic, with rapid and delayed components. Relative to other stimulants of NO production, insulin is rather weak, with 10 to 100 times less maximum effects than acetylcholine. However, it is possible that the delayed-positive effect of insulin on eNOS expression has an important consequence in sustaining the level of eNOS expression, which will have a general effect on all the stimulators of NO production. The mechanism of insulin's effect on NO production appears to be mediated by the activation of PI3K pathway (33). However, the acute effect appears to be an activation of eNOS, whereas the delayed effects are as a result of the upregulation of gene expression for eNOS.

Thus, in the vascular tissues, insulin has a variety of effects, which can be mediated by at least two signaling pathways involving PI3K and Ras-MAP kinase. At physiological concentrations, insulin mediates its effects through the activation of PI3K/Akt pathway, causing actions such as NO production. This effect can be interpreted as anti-atherogenic. In contrast, the effects mediated through Ras-MAP kinase pathway by insulin, for example, stimulation of ECM production; cell proliferation and migration, appears to be pro-atherogenic. The later effect requires the presence of high concentration of insulin that can be observed in insulin-resistant states. We have proposed that the increased risk of atherosclerosis in insulin-resistant states is caused by the loss of insulin's

Table 3

Proposed Mechanisms of the Adverse Effect of Hyperglycemis

Activation of the polyol pathway

Increases in the nonenzymatic glycation products

Activation of DAG-PKC cascade

Increases in oxidative stress

Enhanced flux via the hexosamine metabolism

Vascular inflammation

Altered expression and actions of growth factors and cytokines action on PI3K/Akt pathway activation and the subsequent production of NO, whereas the activation of Ras-MAP kinase pathway remain intact. In support of this theory, we have documented that the activation of PI3K/Akt pathway and eNOS expression by insulin are significantly reduced in microvessels from insulin-resistant Zucker obese rats as compared to that of the healthy lean control rats, whereas the activation of Ras-MAP kinase pathway was not affected (33,39). These results have provided a molecular explanation for the clinical findings that both insulin deficiency (as in type 1 diabetic patients) and insulin-resistant states (as in patients with metabolic syndrome and type 2 diabetes) can lead to an acceleration of CVD.

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