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

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.

Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

“…Therefore, NOX5 may participate in neuronal degeneration mediated by BBB alterations triggered via ROS accumulation that allow to postulate this oxidase as a therapeutic target in cerebral ischemic injury. In our study, these BBB alterations due to NOX5 may not be mediated by increased systolic blood pressure levels [ 38 ] but through other mechanisms, like COX2 activation. To analyze the BBB integrity, we evaluated the cerebral extravasation of fibrin and IgG, and we found a higher tendency of fibrin extravasation in the knock-in mice.…”

“…Moreover, NOX5 is known to potentiate cardiac remodeling and the dysfunction of hypertensive angiotensin II-induced mice expressing NOX5 in the heart under the α-myosin heavy-chain promoter [ 37 ]. Additionally, in another knock-in mouse, which expressed NOX5 under the Tie2 promoter specific to the endothelium and white blood cells, the authors found that chronic NOX5 expression induced elevated systolic blood pressure levels in aging mice [ 38 ]. In our study, no differences in the systolic blood pressure measurements in the aging mice were observed.…”

NO Synthase but not NO, HNO or H2O2 Mediates Endothelium-Dependent Relaxation of Resistance Arteries from Patients with Resistant Cardiovascular Disease

“…In large elastic conduit arteries, endothelial NOS produces NO that causes smooth muscle relaxation via production of cGMP. Superoxide anions produced by NADPH oxidases and mitochondria inhibit this pathway by uncoupling of eNOS, binding and inactivation of NO and damaging sGC (Daiber et al, 2017;Elbatreek et al, 2020;Evgenov, Pacher, Schmidt, Hasko, Schmidt & Stasch, 2006;Forstermann & Munzel, 2006;Monica, Bian & Murad, 2016;Zhang, Murugesan, Huang & Cai, 2020). In addition to NO, NOS can produce HNO and O 2 - (Forstermann & Munzel, 2006;Schmidt, Hofmann, Schindler, Shutenko, Cunningham & Feelisch, 1996).…”

“…Selection of novel circulating factors can be hypothesis-driven and lead to confirmatory studies in dedicated experimental animals. These approaches were recently applied with respect to the role of a subtype of NADPH oxidases (NOX5) in the development of regional endothelial dysfunction and systolic hypertension with ageing (Elbatreek et al, 2020).…”

Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Glucose Homeostasis and Diabetes-Related Endothelial Cell Dysfunction

“…A similar murine model, with increased expression of human Nox5 in the endothelium, has shown age-related severe systolic hypertension, and impaired endothelium-dependent vasodilation, as a result of Nox5-induced uncoupling of eNOS [ 156 ]. Further work within a conditional endothelial NOX5 knock-in mouse, has identified a role for Nox5 in the response to ischaemia as a result of myocardial infarction, with evidence that Nox5-derived ROS may modulate the COX-2 and PGE 2 axis in EC.…”