eNOS, metabolic syndrome and cardiovascular disease

Abstract

Large epidemiologic studies have established that diabetes, hyperlipidemia and obesity all increase the risk for cardiovascular disease. However, the precise mechanisms by which these metabolic disorders increase the propensity to develop atherosclerosis are not known. Recently, the concept of the metabolic syndrome - a constellation of conditions including obesity, hypertension, hyperlipidemia and insulin resistance - has received much attention. Studies on the metabolic syndrome might enable a better understanding of the underlying biological mechanisms that lead to cardiovascular disease. This review focuses on endothelial nitric oxide synthase and summarizes evidence that a reduction in the bioavailability of endothelium-derived nitric oxide serves as a key link between metabolic disorders and cardiovascular risk.

Figure 1

Regulation of eNOS activity and mechanisms of endothelial dysfunction. The bioavailability of NO produced by eNOS might be affected at multiple levels, including (i) eNOS mRNA or protein expression; (ii) availability of L-arginine, its substrate, which might be competed by ADMA; (iii) availability of its cofactors, including BH4, for which GTP cyclohydrolase catalyzes the rate-limiting step; (iv) protein–protein interactions, for example with caveolin (inhibitory; red) or hsp90 (stimulatory; green); (v) post-translational modifications, such as phosphorylation at S1177 by Akt and other kinases (stimulatory; green); and (vi) reaction of NO with superoxide to yield peroxynitrite anion. Abbreviations: ADMA, asymmetric dimethyl arginine; BH4, tetrahydrobiopterin; eNOS, endothelial nitric oxide synthase; GTP, guanosine 5′-triphosphate; hsp90, heat-shock protein 90; NO, nitric oxide; O₂⁻, superoxide; OONO⁻, peroxynitrite anion; PKG, protein kinase G; SOD, superoxide dismutase.

Figure 2

Insulin signaling. Insulin signaling in endothelial cells occurs after insulin binding to the insulin receptor. This causes activation of two separate and parallel pathways: (i) PI3K–Akt and (ii) Ras/Raf/MAP kinase. (i) Akt kinase phosphorylates eNOS at S1177, resulting in increased NO production and vasodilation. (ii) The MAP kinase pathway results in endothelin-1 production and vasoconstriction. In other tissues, these pathways have effects (shown in dark blue lettering). In skeletal muscle (left), the PI3K–Akt pathway results in translocation of GLUT4 and glucose uptake. In vascular smooth muscle (right), the MAP kinase pathway results in growth and mitogenesis. Abbreviations: eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; GLUT4, insulin-dependent glucose transporter 4'; MAP kinase, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3-kinase.

Figure 3

Relationships between insulin resistance, visceral adiposity, and endothelial dysfunction. Insulin 3 resistance can cause endothelial dysfunction through altered PI3K–Akt signaling. Endothelial dysfunction, in turn, can cause insulin resistance owing to diminished blood flow and capillary recruitment, leading to decreased substrate and insulin delivery. Endothelial dysfunction can lead to insulin resistance, as well as visceral adiposity by impaired mitochondrial biogenesis. Visceral adipose tissue can secrete adipokines and FFAs, which can cause endothelial dysfunction and peripheral insulin resistance. Finally, insulin resistance can lead to atherogenic dyslipidemia, which can contribute to visceral obesity. Abbreviations: PI3K, phosphatidylinositol-3-kinase; FFAs, free fatty acids.

Figure 4

Role of eNOS S1177 phosphorylation in integrating effects of multiple mediators. eNOS S1177 is phosphorylated by multiple kinases, including (i) Akt kinase and (ii) AMP kinase. Shear stress, VEGF, insulin, estrogen, statins and leptin all act through Akt kinase to increase S1177 phosphorylation. Adiponectin, resistin and other metabolic signals act through AMP kinase to influence S1177 phosphorylation. (iii) The S1177 unphosphorylated form of eNOS has less enzymatic activity and is associated with lower vascular NO levels than the phosphorylated form. (iv) By contrast, S1177 phosphorylated eNOS is associated with increased vascular reactivity, higher vascular NO levels, and protective effects on vascular smooth muscle proliferation, leukocyte–endothelial interactions and platelet aggregation. Abbreviations: AMP, adenosine monophosphate; eNOS, endothelial nitric oxide synthase; LE, leukocyte–endothelial; plt, platelet; VEGF, vascular endothelial growth factor. The green arrows indicate stimulation of eNOS S1177 phosphorylation, and the red inhibitory signal indicates inhibition of S1177 phosphorylation by resistin.