Physicians' Academy for Cardiovascular Education

Causal mechanism of age-related hypertension endotype identified

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

Literature - Elbatreek MH, Sadegh S, Anastasi E, et al. - PLoS Biol 2020, 18:e3000885, 10.1371/journal.pbio.3000885

Introduction and methods

In 95% of cases with hypertension, the cause remains unknown. Treatment in these patients is focused on symptomatic vasodilation and lifestyle management, but can be ineffective. Treatment-resistant hypertension is observed, high number to treat is required and many patients still suffer from CV events, such as stroke and MI [1].

A mechanism of hypertension that has been proposed for a long time is oxidative stress: an unphysiological production of reactive oxygen species (ROS). ROS interferes with nitric-oxide (NO)-dependent vasodilation of the vessels [2]. However, no hypertension-relevant cellular source of ROS has been identified thus far. Genome-wide association studies (GWAS) [3] and mice studies [4-6] have suggested a role for NAPDH oxidases (NOX), a enzyme family that is responsible for the formation of ROS.

This study investigated the association of NOX with hypertension and NO-dependent vasodilation. This was done by molecular network analysis, investigation of NOX5 levels in hypertensive patients compared to healthy controls and by developing a knock-in mouse model expressing human NOX5.

Main results


This study identified a causal molecular mechanism of age-related hypertension by human genetic, human clinical and genetic preclinical mechanistic validation approaches. The mechanism consists of NOX5-induced uncoupling of endothelial NOS resulting in impaired endothelial-dependent vasodilation of muscular conduit arteries. This mechanism may be a target for curative antihypertensive therapy.


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