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

  • Using 3 complementing unbiased in silico (computational) approaches to identify first neighbors of NOX family members and NO-cGMP-related proteins in a molecular subnetwork revealed that NOX5 is a direct neighbor of endothelial NO-cGMP signaling.
  • In patients with hypertension and normoalbuminuria (n=20) higher NOX5 protein plasma levels were observed compared to normotensive individuals (n=10), and among patients with hypertension those with microalbuminuria (n=20) had highest NOX5 protein levels. A subgroup analysis showed that approximately every fourth hypertensive patient would have this high NOX5 mechanotype.
  • In young mice of a knock-in (KI) mouse model expressing human NOX5 in the endothelium 9 (n=19), SBP, DBP and mean arterial pressure (MAP) were similar to those of wild-type mice (n=20). Upon aging of mice, SBP and MAP was significantly elevated in KI mice (n=33) compared to wild-type mice (n=31) and DBP remained unmodified.
  • Experiments with thoracic aorta, femoral artery, and saphenous artery isolated from aged KI (n=9) and wildtype mice (n=9) were performed and suggest that endothelial NOX5 induces uncoupling of endothelial NO synthase (NOS). Uncoupling of NOS occurs when ROS oxidize a NOS cofactor, resulting in decreased NO formation. This leads to impaired endothelium-dependent dilation of muscular conduit arteries, resulting in systolic hypertension.


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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2. Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986; 320(6061):454–6.

3. Kraja AT, Cook JP, Warren HR, Surendran P, Liu C, Evangelou E, et al. New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. Circ Cardiovasc Genet. 2017; 10(5).

4. Yogi A, Mercure C, Touyz J, Callera GE, Montezano AC, Aranha AB, et al. Renal redox-sensitive signaling, but not blood pressure, is attenuated by Nox1 knockout in angiotensin II-dependent chronic hypertension. Hypertension. 2008; 51(2):500–6.

5. Murdoch CE, Alom-Ruiz SP, Wang M, Zhang M, Walker S, Yu B, et al. Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction. Basic Res Cardiol. 2011; 106(4):527–38.

6. Sag CM, Schnelle M, Zhang J, Murdoch CE, Kossmann S, Protti A, et al. Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NADPH Oxidase 2 on Blood Pressure. Circulation. 2017; 135 (22):2163–77. .

Find this article online at PLoS Biol

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