Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5

Abstract

The Noxes (NADPH oxidases) are a family of ROS (reactive oxygen species)-generating enzymes. Of the seven family members, four have been identified as important sources of ROS in the vasculature: Nox1, Nox2, Nox4 and Nox5. Although Nox isoforms can be influenced by the same stimulus and co-localize in cellular compartments, their tissue distribution, subcellular regulation, requirement for cofactors and NADPH oxidase subunits and ability to generate specific ROS differ, which may help to understand the multiplicity of biological functions of these oxidases. Nox4 and Nox5 are the newest isoforms identified in the vasculature. Nox4 is the major isoform expressed in renal cells and appear to produce primarily H2O2. The Nox5 isoform produces ROS in response to increased levels of intracellular Ca2+ and does not require the other NADPH oxidase subunits for its activation. The present review focuses on these unique Noxes, Nox4 and Nox5, and provides novel concepts related to the regulation and interaction in the vasculature, and discusses new potential roles for these isoforms in vascular biology.

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…While the functional roles for each of these variants have yet to be discovered, all share a number of features common to all Noxs, including six transmembrane spanning domains, two groups of heme-spanning histidines, an NADPH-binding motif, and an FAD-binding domain. Vascular Nox5 is activated by PDGF, Ang II, and ET-1 and it involves ERK1/2, PI(4, 5)P2, PKC, and c-Abl (17, 137,155). Hsp90 binds to and regulates Nox5 protein stability (56,126,33).…”

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

“…Unlike the other vascular Nox isoforms, Nox5 gene is absent in rodents; it generates ROS from a single gene product and does not require classical NADPH oxidase subunits (p22phox, p47phox, and p67phox) for its activation 15. Nox5 is the only Nox isoform that has been crystalized 16.…”

Drug Treatment of Hypertension: Focus on Vascular Health

“…Increased PWV occurs mainly in the pre-hypertensive phase, suggesting that vascular changes may precede the onset of established hypertension 6 . Increased PWV predicts increased risk of cardiovascular morbidity and mortality in patients with hypertension, diabetes mellitus and end-stage renal 69,66 . PWV may therefore be a useful marker to identify patients in the early pre-hypertensive phase and allow lifestyle changes to be implemented, alongside blood pressure lowering medication if necessary, to prevent worsening high blood pressure and the development of hypertension.…”