Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension

Abstract

Reduced nitric oxide bioavailability contributes to endothelial dysfunction and hypertension. The endothelial isoform of nitric oxide synthase (eNOS) is responsible for the production of nitric oxide within the endothelium. Loss of eNOS cofactor tetrahydrobiopterin to initial increase in oxidative stress leads to uncoupling of eNOS, in which the enzyme produces superoxide anion rather than nitric oxide, further substantiating oxidative stress to induce vascular pathogenesis. The current review focuses on recent advances on the molecular mechanisms and consequences of eNOS dysfunction in hypertension, and potential novel therapeutic strategies restoring eNOS function to treat hypertension.

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Figure 1

Endothelial dysfunction by eNOS uncoupling. Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO) to mediate vasorelaxation and preservation of vascular function. Tetrahydrobiopterin (H4B) is the key cofactor responsible for normal electron transfer from the reductase domain of one eNOS monomer to the oxygenase domain of the other monomer to produce NO, and in its deficiency, eNOS produces superoxide rather than NO, a process now referred to as eNOS uncoupling. H4B can be supplied by both de novo biosynthesis and salvage pathways. It is newly synthesized from GTP by activations of sequential enzymes of GTP hydrocyclolase 1 (GTPCH1), PTP synthase (PTPS), and sepiapterin reductase (SPR), or restored from its oxidized form H2B by the salvage enzyme dihydrofolate reductase (DHFR). SPR can also catalyze conversion of H4B precursor sepiapterin to H2B, prior to its conversion to H4B by DHFR. Pathological stimuli such as Ang II activates NADPH oxidase isoform 1 (NOX1) to produce superoxide in endothelial cells, which in turn cause peroxynitrite dependent oxidation of H4B and hydrogen peroxide dependent DHFR deficiency, leading to persistent reduction in H4B bioavailability. Superoxide production by uncoupled eNOS further sustains oxidative stress in the vasculature, resulting in endothelial dysfunction, impaired endothelium-dependent vasorelaxation, and elevated blood pressure.