Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Abstract

Background: Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice overexpressing ET-1 exhibit normal blood pressure. We hypothesized that in states of ET-1 overproduction, the lack of counterregulatory mediators such as nitric oxide (NO), produced by the inducible NO synthase (iNOS), may critically impair endothelial function and may result in blood pressure elevation. Methods: We generated crossbred animals of ET transgenic mice (ET+/+) and iNOS knockout mice (iNOS–/–) and evaluated blood pressure and endothelial function in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine, sodium nitroprusside, and ET-1, alone or in the presence of BQ123 or BQ788. Results: Systolic blood pressure was similar in ET+/+, iNOS–/– and wild-type mice, but was significantly elevated in ET+/+ iNOS–/– crossbred animals versus ET+/+ mice. Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (95 ± 5 vs. 78 ± 5% of preconstriction in wild-type littermates; p < 0.05). Additional knockout of iNOS led to a significant decrease of endothelium-dependent relaxation in combined ET+/+ iNOS–/– animals (75 ± 6%; p < 0.05 vs. ET+/+ mice). Endothelium-independent relaxation was comparable among all groups. Maximum vascular contraction to ET-1 was reduced in ET+/+ mice (33 ± 4%), iNOS–/– mice (38 ± 5%) and ET+/+ iNOS–/– mice (44 ± 4%) to a similar extent as compared with wild-type littermates (66 ± 4%; p < 0.05). Conclusions: Our data show for the first time that in transgenic mice overexpressing human ET-1, additional knockout of iNOS results in impaired endothelium-dependent vasodilatation thus contributing to elevated blood pressure in ET+/+ iNOS–/– animals.

Pathophysiology of the endothelin system - lessons from genetically manipulated animal models

“…Compared to the normotensive wild type and ET+/+, the crossbred ET+/+ eNOS KO have a significantly elevated blood pressure. This is also seen in ET+/+ inducible NOS KO crossbreds [11] which corroborates the hypothesis that the NO system counterregulates the ET overexpression in the ET-1 transgenic model leading to a normotensive phenotype.…”

Protective effect of soluble fiber from Undaria pinnatifida on vascular endothelium in hypercholesterolemic rabbits

“…Studies in clinics have shown that administration of big ET-1 results in improved vasoconstriction and increased formation of ET-1 in patients with atherosclerosis (Bo¨hm et al 2002). Studies carried out in animals have showed that in transgenic mice overexpressing human ET-1 results in impaired endothelium-dependent (Quaschning et al 2008). The results of the present study showed that endothelium-dependent vasorelaxation was impaired concomitantly with increase of ET-1 and MDA levels in hypercholesterolemic rabbits.…”

“…There is substantial evidence to suggest that endogenous ET-1 is also involved in the development of endothelial dysfunction in atherosclerosis (Bo¨hm et al 2002;Quaschning et al 2008). Studies in clinics have shown that administration of big ET-1 results in improved vasoconstriction and increased formation of ET-1 in patients with atherosclerosis (Bo¨hm et al 2002).…”

Patients with Chronic Coronary Syndrome Can Benefit from Consumption of Enriched Chicken Eggs: The Effects on Microvascular Function, Inflammatory Biomarkers, and Oxidative Status—Randomized Clinical Study

“…However, in the present study, no alterations in oxidative stress biomarkers were detected in any of the dietary protocols. In transgenic mice overexpressing human endothelin-1 (ET-1), the knockout of iNOS resulted in impaired endothelium-dependent vasodilation [51]. Although the increased expression of iNOS was thought to contribute to the occurrence of cardiogenic shock in individuals with myocardial infarction, iNOS inhibitors did not show beneficial effects in this group of individuals.…”