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Review
. 2019 Aug 2;20(15):3775.
doi: 10.3390/ijms20153775.

Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

Cesar A Meza  1 , Justin D La Favor  1 , Do-Houn Kim  1 , Robert C Hickner  2   3   4
Affiliations
Review

Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

Cesar A Meza et al. Int J Mol Sci. .

Abstract

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

Keywords: NADPH oxidase; ROS; eNOS; endothelium; glucose; hyperglycemia; insulin resistance; obesity; reactive oxygen species; type 2 diabetes; vascular function.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of endothelial nitric oxide synthase (eNOS) uncoupling leading to endothelial dysfunction. (Left panel) Shear stress and acetylcholine (Ach) increase calcium concentrations to mediate calcium-calmodulin (CaM)-dependent and protein kinase A (PKA)-dependent activation of eNOS. PKA phosphorylates eNOS at the Ser-1177/Ser-1179 residue and heat shock protein 90 (hsp90) maintains the eNOS activating conformation as well as releases eNOS from calveolin-1 (Cav-1) at the plasma membrane. L-arginine and molecular oxygen (O2) catalyze the activation of eNOS, with the cofactors tetrahydrobiopterin (BH4), FMN, FAD, and NADPH (not shown), to produce nitric oxide (NO) and L-citrulline. NO diffuses across the endothelium and targets soluble guanylyl cyclase (sGC) to induce cyclic GMP-dependent activation of protein kinase G (PKG) in vascular smooth muscle cells. The subsequent reduction of intracellular calcium concentrations leads to vasodilation. The NADPH Oxidases 1, 2, and 5 (NOX1, 2, 5) generate superoxide (O2−), while NOX4 produces hydrogen peroxide (H2O2) that crosses the plasma membrane and is scavenged by glutathione peroxidase (GPx) (t-bar). (Right panel) However, oxidative stress leads to eNOS uncoupling and endothelial dysfunction. Dysfunctional eNOS activation results in O2− production, rather than NO, as shown by the red dashed line. Peroxynitrite (ONOO−) is rapidly generated from a reaction between O2− and NO, and potentiates eNOS uncoupling. Oxidation of BH4 to dihydrobiopterin (BH2) (red dashed lines) by ONOO− and H2O2 limits eNOS substrate availability, and prevents NO production. Further, ONOO− oxidizes the zinc thiolate (ZnS4) core of eNOS and disrupts dimerization. Uncoupling of eNOS, therefore, creates a toxic cycle of oxidative stress that reduces NO bioavailability and elicits endothelial dysfunction.
Figure 2
Figure 2
Vascular insulin resistance. There is a reciprocal balance between the divergent branches of endothelial insulin transduction. Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the preferential activation of the Raf/MAPK pathway in vascular insulin resistance leads to excessive vasoconstriction, reduced insulin-stimulated blood flow and reduced insulin-stimulated skeletal muscle glucose disposal.
Figure 3
Figure 3
Endothelial NADPH oxidase (NOX) isoforms. The primary function of NOX is the generation of reactive oxygen species (ROS). All four endothelial NOX isoforms are comprised of a catalytic subunit, and NOX1, 2, and 4 require additional subunits for activation. There are several protein-protein interactions involved in producing NOX activity, including interactions between the transmembrane catalytic (i.e., NOX1, NOX2, etc.) and stabilizing (p22phox) subunits with cytosolic organizer (NOXO1/p47phox) and activator (NOXA1/p67phox) subunits. The small GTPase, Rac1, tethers the activator to the plasma membrane, while the organizer acts as a scaffold to maintain interactions between subunits. In contrast, NOX4 is constitutively active in the presence of p22phox and its cytosolic regulator protein polymerase delta-interacting protein 2 (Poldip2). NOX5 does not require additional subunits, and phosphorylation of its cytosolic domain increases the sensitivity to calcium. The electron transfer of cytosolic NADPH to extracellular molecular oxygen generates superoxide (O2−) in NOX1, 2, and 5, and hydrogen peroxide (H2O2) in NOX4.
Figure 4
Figure 4
Mechanisms of NOX activation in hyperglycemic conditions. Exposure of cultured endothelial cells to high glucose concentrations elicits activation of NADPH oxidases (NOX). The interactions between specific NOX isoforms and downstream signaling events that lead to endothelial dysfunction are incompletely understood; although several mediators of dysfunctional eNOS activation have been identified. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been reported as a direct activator of NOX4 and a stimulus of NOX1 activation. In contrast, the AMP-activated protein kinase (AMPK) inhibits NF- κB-mediated activation of NOX by preventing proteasomal degradation of the NF-κB inhibitor (IκB). Protein kinase C (PKC) is activated by oxidative stress and phosphorylates the NOX1 and NOX2 subunits (p47phox, p67phox) to further increase superoxide production. In addition, hyperglycemia-induced oxidative stress depletes the eNOS cofactor, tetrahydrobiopterin (BH4), which promotes eNOS uncoupling and enhances superoxide levels. Subsequent peroxynitrite (ONOO−) generation oxidizes and promotes proteasomal degradation of the BH4 rate-limiting enzyme, guanosine 5′-triphosphate cyclohydrolase I (GTPCH). While hydrogen peroxide (H2O2) can increase insulin signaling by inhibiting the protein-tyrosine phosphatase-1B (PTP1B), type 2 diabetes may impair the beneficial features of NOX4-mediated H2O2 production and prevent activation of phosphoinositide 3 kinase (PI3K) by insulin receptor substrate 1/2 (IRS1/2); Akt indicates protein kinase B, BH2, dihydrobiopterin.
Figure 5
Figure 5
Endothelial dysfunction in type 2 diabetes. Increased NOX activation in settings of type 2 diabetes leads to several vascular and metabolic impairments. Hyperglycemia and hyperinsulinemia are major stimuli of endothelial NOX activation, which contributes to a cytotoxic cycle of oxidative stress and eNOS uncoupling. The altered redox environment subsequently reduces the ability of insulin to perform vasodilatory and glucose transport actions, rendering an essential decrement of endothelial function. Based on human studies, endothelial dysfunction precedes the development of type 2 diabetes, and animal models of type 2 diabetes demonstrate that experimental manipulation of NOX is an effective strategy to mitigate endothelial dysfunction and insulin resistance.
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