Search

Cardiovascular diseases are among the leading causes of death worldwide. Reactive oxygen species (ROS) can act as damaging molecules but also represent central hubs in cellular signalling networks. Increasing evidence indicates that ROS play an important role in the pathogenesis of cardiovascular diseases, although the underlying mechanisms and consequences of pathophysiologically elevated ROS in the cardiovascular system are still not completely resolved. More recently, alterations of the epigenetic landscape, which can affect DNA methylation, post-translational histone modifications, ATP-dependent alterations to chromatin and non-coding RNA transcripts, have been considered to be of increasing importance in the pathogenesis of cardiovascular diseases. While it has long been accepted that epigenetic changes are imprinted during development or even inherited and are not changed after reaching the lineage-specific expression profile, it becomes more and more clear that epigenetic modifications are highly dynamic. Thus, they might provide an important link between the actions of ROS and cardiovascular diseases. This review will provide an overview of the role of ROS in modulating the epigenetic landscape in the context of the cardiovascular system.This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

Increased levels of reactive oxygen species (ROS) contribute to vascular diseases like pulmonary hypertension and atherosclerosis. Although a NOX2-containing NADPH oxidase similar to the neutrophil one has been described to be active in endothelial cells, the contribution of newly discovered NOX homologues (NOX1-NOX5) was still unclear. Therefore, the overall aim of this study was to better characterize the expression, regulation and function of NOX homologues in different endothelial cell models. First, we could demonstrate the presence of NOX1, NOX2, NOX4, NOX5 including NOX5S as well as p22phox mRNA and protein levels in Ea.Hy926 or HMEC-1 cells. Furthermore, NOX5 protein was also present in endothelial and smooth muscle cells in the vascular wall of spleen and lung tissue. We found that NOX2, NOX4 and NOX5 were present in an intracellular perinuclear compartment, whereby NOX2 and NOX4 could be localized simultaneously in one cell. NOX2, NOX4, NOX5 were able to interact with p22phox and overexpression of NOX2, NOX4 and NOX5 increased ROS generation, although NOX5-dependent ROS generation did not require the presence of p22phox. NOX2, NOX4 and NOX5 also increased endothelial proliferation while depletion of NOX2, NOX4 and NOX5 decreased ROS generation, proliferation and tube forming ability indicating angiogenic activity under basal conditions. NOX2- and NOX4-induced proliferation was mediated by p38 MAP kinase. Although NOX1 expression as well as the expression of its regulatory subunits NOXO1 and NOXA1 was detectable in endothelial cells, depletion of NOX1 did not significantly affect basal ROS generation or proliferation of endothelial cells. Second, we could demonstrate the upregulation of NOX2, NOX5 and NOX5S after thrombin stimulation in endothelial cells and the modulation of p22phox expression in an ATF4- and XBP1-dependent manner under ER-stress conditions. Cellular stress either by thrombin or UPR also induced ROS generation of endothelial cells. In addition, thrombin induced proliferation and enhanced the tube forming ability of endothelial cells. Thrombin-induced ROS generation, proliferation and tube forming ability were diminished by silencing NOX2 or NOX5, whereas UPR induced ROS generation was inhibited by silencing p22phox as well as by silencing ATF4 or XBP1. In summary, this work provides evidence that in endothelial cells, NOX2, NOX4 and NOX5, but not NOX1, contribute to basal ROS generation, proliferation and angiogenesis and that the NOX proteins NOX2 and NOX5 as well as p22phox play an important role in the response to thrombin and ER-stress providing new insights in endothelial function and redox signaling.