Identification of causal mechanism of age-related hypertension endotype
NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and therapeutic target of an age-related hypertension endotype
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 .
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 . However, no hypertension-relevant cellular source of ROS has been identified thus far. Genome-wide association studies (GWAS)  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.
- 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.