Targeting NADPH oxidases in vascular pharmacology

Abstract

Oxidative stress is a molecular dysregulation in reactive oxygen species (ROS) metabolism, which plays a key role in the pathogenesis of atherosclerosis, vascular inflammation and endothelial dysfunction. It is characterized by a loss of nitric oxide (NO) bioavailability. Large clinical trials such as HOPE and HPS have not shown a clinical benefit of antioxidant vitamin C or vitamin E treatment, putting into question the role of oxidative stress in cardiovascular disease. A change in the understanding of the molecular nature of oxidative stress has been driven by the results of these trials. Oxidative stress is no longer perceived as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production. NADPH oxidases are at the center of these events, underlying the dysfunction of other oxidases including eNOS uncoupling, xanthine oxidase and mitochondrial dysfunction. Thus NADPH oxidases are important therapeutic targets. Indeed, HMG-CoA reductase inhibitors (statins) as well as drugs interfering with the renin-angiotensin-aldosterone system inhibit NADPH oxidase activation and expression. Angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists (sartans) and aliskiren, as well as spironolactone or eplerenone, have been discussed. Molecular aspects of NADPH oxidase regulation must be considered, while thinking about novel pharmacological targeting of this family of enzymes consisting of several homologs Nox1, Nox2, Nox3, Nox4 and Nox5 in humans. In order to properly design trials of antioxidant therapies, we must develop reliable techniques for the assessment of local and systemic oxidative stress. Classical antioxidants could be combined with novel oxidase inhibitors. In this review, we discuss NADPH oxidase inhibitors such as VAS2870, VAS3947, GK-136901, S17834 or plumbagin. Therefore, our efforts must focus on generating small molecular weight inhibitors of NADPH oxidases, allowing the selective inhibition of dysfunctional NADPH oxidase homologs. This appears to be the most reasonable approach, potentially much more efficient than non-selective scavenging of all ROS by the administration of antioxidants.

Luteolin Protects HUVECs from TNF-α-induced Oxidative Stress and Inflammation via its Effects on the Nox4/ROS-NF-κB and MAPK Pathways

“…The sustained activation of NADPH oxidase in patients with atherosclerosis may diminish the intracellular levels of NADPH, an essential cofactor for endothelial NO synthase (eNOS) and several antioxidant systems 8,9) . Nox4 is significantly more abundant than other Nox isoforms in cardiovascular tissues, while p22phox is a critical component of NADPH oxidase, which regulates the activation of NADPH oxidase 8,27,28) . Therefore, both of these molecules are critical subunits for NADPH oxidase and play critical roles in the pathogenesis of oxidative stress.…”

Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

“…As the standard therapeutics in RA, TNF-␣ antagonists, and disease modifying anti-rheumatic drugs have only a limited success in prevention of cardiovascular events, the additional use of antioxidative drugs could be an alternative. In numerous clinical trials the usage of nutritional supplements (such as ␤-carotene, selenium, vitamin C, and vitamin E) as antioxidative substances in the prevention of coronary heart disease and stroke resulted in conflicting data (positive, neutral, and negative) (69,70). Therefore more specific drugs acting via down-regulation of Nox could be promising.…”

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

“…Major sources of ROS are thought to be eNOS-uncoupling and NADPH oxidase [41] CGRP has been shown to activate eNOS via the cAMP-PKA [42] and AMPK [43] pathways.…”