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Review
. 2009 Sep 29;120(13):1266-86.
doi: 10.1161/CIRCULATIONAHA.108.835223.

Molecular insights and therapeutic targets for diabetic endothelial dysfunction

Jian Xu  1 , Ming-Hui Zou
Affiliations
Review

Molecular insights and therapeutic targets for diabetic endothelial dysfunction

Jian Xu et al. Circulation. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Endothelium, as a complex endocrine and paracrine organ, plays a crucial role in the maintenance of vascular homeostasis. Far beyond being simply a physical barrier between the blood and vascular wall, the endothelium is now recognized as the most important component of normal vascular homeostasis, through which the anticoagulant, antiplatelet, and fibrinolytic phenotypes of vascular cells can be maintained. Essentially, the maintenance of vascular homeostasis by endothelium is accomplished through the release of vasoprotective factors (eg, NO/endothelium-derived relaxing factor, prostacyclin, bradykinin, and endothelium-derived hyperpolarizing factor [EDHF]) and harmful substances (eg, endothelin [ET], ROS, endothelium-derived COX-dependent vasoconstricting factor [EDCF], and angiotensin II [Ang II]). Damage to endothelium will disrupt the balance between vasoprotective factors and harmful substances, initiating a number of events/processes that promote or exacerbate atherosclerosis via increased endothelial permeabilization, platelet aggregation, leukocyte adhesion, and cytokine production.
Figure 2
Figure 2
Origin of endothelial dysfunction in diabetes mellitus. Endothelial dysfunction in diabetes can be induced solely by or by a combination of (1) hyperglycemia, (2) fatty acids, (3) inflammation, and (4) insulin resistance. Prolonged exposure to hyperglycemia is now recognized as a major factor in the pathogenesis of diabetic complications, including atherosclerosis, mechanistically involving enhanced enzymatic and nonenzymatic protein/lipid glycosylation, protein kinase C activation, inflammation, and ROS production. Other factors including dyslipidemia, elevated FFAs, inflammation, and insulin resistance, can cause endothelial dysfunction. RNS indicates reactive nitrogen species; EDCF, endothelium-derived COX-dependent vasoconstricting factor; AGE, advanced glycation end products; and PKC, protein kinase C.
Figure 3
Figure 3
Insulin resistance induces endothelial dysfunction in diabetes. In addition to crucial metabolic actions, insulin plays a critical role in the maintenance of physiological endothelial function through its ability to stimulate NO release via a cascade of signaling, initiated by binding to its cognate receptor (IR) expressed on endothelial cells. The cascade involves activation of the PI3K-Akt axis and downstream serine 1177 phosphorylation of eNOS for NO-dependent vasodilator actions or stimulation of the endothelial release of ET-1 for its vasoconstrictor effect. In insulin-resistance vessels, pathway-specific impairments in PI3K-dependent signaling decrease the expression and activity of eNOS, whereas compensatory secretion of insulin augment its mitogen-activated protein kinase pathways, which results in both the overexpression of adhesion molecules (vascular cell adhesion molecule-1 and E-selectin) and increased secretion of ET-1. Insulin-resistant endothelium becomes highly inflammatory, with impaired blood supply, which in turn worsens insulin resistance. SHC indicates Src[sarcoma] Homology domain C-terminal; PDK-1, phosphoinositide-dependent kinase-1; MEK, MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) kinase; MAPK, mitogen-activated protein kinase; VCAM, vascular cell adhesion molecule;.
Figure 4
Figure 4
Generation of ROS and reactive nitrogen species in endothelial cells. ONOO− is formed by the diffusion-limited radical-radical reaction between O2•− and NO. The diffusion-limited reaction means that every time NO bumps into O2•− (which is controlled by diffusion), the 2 produce ONOO−. Because NO is 1000 times smaller than CuZn-SOD, it diffuses faster and therefore reacts with superoxide at least 10 times faster than SOD can possibly scavenge O2•−. Thus, many of the biological effects attributed to NO are in fact mediated by ONOO−.
Figure 5
Figure 5
ONOO−-mediated tyrosine nitration of prostacyclin synthase contributes to vascular complications in diabetes mellitus. In diabetes, hyperglycemia or hyperlipidemia increases O2•− and ONOO− generation, which results in PGIS nitration and subsequent TPr stimulation. The formation of ONOO− not only decreases the protective actions of both NO and PGI2 but also releases endothelium-derived COX-dependent vasoconstriction factor (EDCF) via the accumulation of nonmetabolized PGH2. Thus, ONOO−-mediated PGIS nitration tips the balance toward platelet aggregation, atheroma accumulation, and thrombus formation. AA indicates arachidonic acid; TP receptor, TXA2/PGH2 receptor.
Figure 6
Figure 6
ONOO− causes eNOS uncoupling through multiple pathways. Diabetes via hyperglycemia- or dyslipidemia-derived O2•− and then ONOO− enhances (1) BH4 oxidation into dihydrobiopterin (BH2), (2) oxidation of the zinc-thiolate cluster of eNOS, which results in zinc-depleted eNOS dimers, which have reduced affinity toward both BH4 and L-arginine, and (3) ubiquitination and proteasomal degradation of GTPCH1, a rate-limiting enzyme in de novo synthesis of BH4, an essential cofactor of eNOS.
Figure 7
Figure 7
Mechanism of ONOO−-mediated insulin resistance in diabetic vessels. ONOO− can cause tyrosine nitration of PI3K or insulin receptor substrate-1 (IRS-1) to prevent their activation, which results in a reduction of both IRS-1 and PI3K-Akt signaling. in addition, ONOO− generated during hyperglycemia exposure via the tumor suppressor LKB1 via Rho/Rho-associated kinase–dependent signaling pathways causes insulin resistance by increasing the phosphorylation and activity of PTEN. PDK indicates phosphoinositide-dependent kinase.
Figure 8
Figure 8
AMPK as an emerging therapeutic target for promoting vascular health in diabetes mellitus.
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