NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype.

Mahmoud H Elbatreek,Tim Kacprowski,Andreas Teubner,Chien-Yi Hsu,Jan Baumbach,Elisa Anastasi,Harald H H W Schmidt,Paul M H Schiffers,Emre Guney,Cristian Nogales,Po-Hsun Huang,Pamela W M Kleikers,Ahmed A Hassan,Anil Wipat,Sepideh Sadegh,Jo G R De Mey,Ger M Janssen

doi:10.1371/journal.pbio.3000885

Abstract

Hypertension is the most important cause of death and disability in the elderly. In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS forming NADPH oxidase (Nox) genes associate with hypertension, yet target validation has been negative. We re-investigate this association by molecular network analysis and identify NOX5, not present in rodents, as a sole neighbor to human vasodilatory endothelial nitric oxide (NO) signaling. In hypertensive patients, endothelial microparticles indeed contained higher levels of NOX5-but not NOX1, NOX2, or NOX4-with a bimodal distribution correlating with disease severity. Mechanistically, mice expressing human Nox5 in endothelial cells developed-upon aging-severe systolic hypertension and impaired endothelium-dependent vasodilation due to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling of endothelial NOS is a causal mechanism and theragnostic target of an age-related hypertension endotype. Nox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.

Highlights

Hypertension is of major medical relevance as a risk factor for myocardial infarction, stroke, and other chronic conditions and death [1]
This resulted in a disease module consisting of several connected components, which revealed that all NADPH oxidase (NOX) isoforms but NOX5 were excluded as a close neighbor of endothelial nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling
This endotype affects approximately one in 4 patients and molecularly consists of a NOX5-induced uncoupling of endothelial NO synthase (NOS) followed by impaired endothelium-dependent vasodilation in muscular conduit arteries

Summary

Introduction

Hypertension is of major medical relevance as a risk factor for myocardial infarction, stroke, and other chronic conditions and death [1]. Except for 5% of patients with secondary hypertension (due to renal artery stenosis, adrenal adenomas, pheochromocytomas, and numerous single-gene mutations involving renal transporters [2]), the cause of hypertension remains unknown in the remaining 95% of all cases. In these cases of so-called ‘essential hypertension,’ treatments have to focus on symptomatic vasodilatory drug therapy and lifestyle management. Even this symptomatic antihypertensive therapy is sometimes ineffective, i.e., in treatmentresistant hypertension, and requires a high number to treat, with many patients still experiencing adverse outcomes such as stroke and myocardial infarction [3]. No hypertension-relevant cellular source of ROS, has been identified to either prove this hypothesis or exploit it for a mechanism-based or even curative clinical therapy

Methods

Results

Conclusion