HIF-1α during hypoxia and oxidative stress
Low oxygen conditions (hypoxia) are a characteristic of atherosclerotic lesions, as the microenvironment is associated with increased energy demand and diminished vascular oxygen supply. The main mechanism by which cells respond to hypoxia is by activation of the transcription factor HIF-1α, regulating more than 200 HIF-1 target genes which are responsible for angiogenesis, survival and metabolism and include VEGF, erythropoetin, factors contributing to modulation of extracellular matrix and thrombosis such as PAI-1, the glucose transporters of the GLUT family, glycolytic enzymes and nitric oxide synthase (NOS).
Despite its stabilization during hypoxia, HIF-1α protein has also been shown to be upregulated under normoxia in response to reactive oxygen species (ROS), NO, cytokines, and growth factors. Oxidative modification of LDL by ROS has been proposed as an early and crucial step in the development of atherosclerosis. We aim to describe the effect of oxidatively modified lipoproteins (oxLDL) on HIF-1α activation.
Beside NO and CO, H2S (hydrogen sulfide) was recently identified as the third endogenous gasotransmitter. H2S has been found to inhibit leukocyte-endothelial cell interactions, inhibit cellular apoptosis, could act as an antioxidant and possesses vasorelaxing properties.
Whether H2S plays a part in the control of HIF-1α mediated cell signaling pathways has yet to be addressed. Currently, we are interested in the impact of antioxidant defense agents like vitamin C or H2S on HIF-1α activation during hypoxia and oxLDL induced oxidative stress in a cell culture model for macrophages.