Oxidases and peroxidases in cardiovascular and lung disease: New concepts in reactive oxygen species signaling

Abstract

Reactive oxygen species (ROS) are involved in numerous physiological and pathophysiological responses. Increasing evidence implicates ROS as signaling molecules involved in the propagation of cellular pathways. The NADPH oxidase (Nox) family of enzymes is a major source of ROS in the cell and has been related to the progression of many diseases and even in environmental toxicity. The complexity of this family’s effects on cellular processes stems from the fact that there are 7 members, each with unique tissue distribution, cellular localization and expression. Nox proteins also differ in activation mechanisms and the major ROS detected as their product. To add to this complexity, mounting evidence suggests that other cellular oxidases or their products may be involved in Nox regulation. The overall redox and metabolic status of the cell, specifically the mitochondria, also has implications on ROS signaling. Signaling of such molecules as electrophillic fatty acids has impact on many redox sensitive pathologies, and thus, as anti-inflammatory molecules, contributes to the complexity of ROS regulation. The following review is based on the proceedings of a recent international Oxidase Signaling Symposium at the University of Pittsburgh’s Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, and encompasses further interaction and discussion among the presenters.

Binding of EBP50 to Nox organizing subunit p47 phox is pivotal to cellular reactive species generation and altered vascular phenotype

“…Moreover, ex vivo incubation of aortas with AngII showed a significant increase in O 2 •− in WT but not EBP50 or Nox1 nulls. Similarly, lipopolysaccharide (LPS)-induced oxidative stress was attenuated in femoral arteries from EBP50 KO vs. WT.…”

“…Under physiological conditions, ROS participate in key signaling pathways leading to distinct phenotypes including those characterized by cell migration, proliferation, differentiation, tissue remodeling, and apoptosis (1)(2)(3). Additionally, ROS mediate cell and tissue oxidative stress and damage at supraphysiological levels (2,4,5). The family of NADPH oxidase proteins (Nox) is widely recognized as one of the most robust and critical sources of the ROS superoxide anion (O 2…”

“…•-) (2,4). Of the 7 Nox isoforms, the Nox1 oxidase is unique in that it comes in two varieties, a canonical and a hybrid system.…”

“…Of the 7 Nox isoforms, the Nox1 oxidase is unique in that it comes in two varieties, a canonical and a hybrid system. Canonical Nox1 is composed of Nox1, p22 phox , Nox organizing subunit 1 (NoxO1), Nox activating subunit 1 (NoxA1), and the small GTPase Rac1 (2). The hybrid Nox1 system employs the classical organizing subunit p47 phox in lieu of its more recently discovered counterpart NoxO1(6-9).…”

“…The hybrid Nox1 system employs the classical organizing subunit p47 phox in lieu of its more recently discovered counterpart NoxO1(6-9). Phosphorylation of p47 phox confers inducibility to the hybrid Nox1 oxidase, in contrast to the constitutively active canonical Nox1 oxidase (2,6,7,9). Nox1 participates in the many vascular pathologies throughout the body including neointimal formation, smooth muscle hypertrophy, and vascular inflammation, among others (4,9).…”