Novel role of protein disulfide isomerase in the regulation of NADPH oxidase activity: pathophysiological implications in vascular diseases.
Vascular cell NADPH oxidase complexes are key sources of signaling reactive oxygen species (ROS) and contribute to disease pathophysiology. However, mechanisms that fine-tune oxidase-mediated ROS generation are incompletely understood. Besides known regulatory subunits, upstream mediators and scaffold platforms reportedly control and localize ROS generation. Some evidence suggest that thiol redox processes may coordinate oxidase regulation. We hypothesized that thiol oxidoreductases are involved in this process. We focused on protein disulfide isomerase (PDI), a ubiquitous dithiol disulfide oxidoreductase chaperone from the endoplasmic reticulum, given PDI's unique versatile role as oxidase/isomerase. PDI is also involved in protein traffic and can translocate to the cell surface, where it participates in cell adhesion and nitric oxide internalization. We recently provided evidence that PDI exerts functionally relevant regulation of NADPH oxidase activity in vascular smooth muscle and endothelial cells, in a thiol redox-dependent manner. Loss-of-function experiments indicate that PDI supports angiotensin II-mediated ROS generation and Akt phosphorylation. In addition, PDI displays confocal co-localization and co-immunoprecipitates with oxidase subunits, indicating close association. The mechanisms of such interaction are yet obscure, but may involve subunit assembling stabilization, assistance with traffic, and subunit disposal. These data may clarify an integrative view of oxidase activation in disease conditions, including stress responses.
Laurindo
Francisco R M
FR
Vascular Biology Laboratory, Heart Institute InCor, University of São Paulo School of Medicine, Brazil. expfrancisco@incor.usp.br
Fernandes
Denise C
DC
Amanso
Angélica M
AM
Lopes
Lucia R
LR
Santos
Célio X C
CX
D004730:Endothelium, Vascular / Q000201:enzymology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014652:Vascular Diseases / Q000209:etiology*
D013438:Sulfhydryl Compounds; D019255:NADPH Oxidases; D019704:Protein Disulfide-Isomerases