Hypoxia in atherosclerosis and inflammation

Abstract

Recent studies underscore the proatherogenic role of hypoxia in macrophage lipid and glucose metabolism, inflammation and polarization. These studies provide new insights into the pathogenesis of atherosclerosis and unravel novel therapeutic targets and new options for noninvasive imaging of human atherosclerotic plaques.

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

“…The molecular pattern of growth factors able to participate in neo-angiogenesis [29] and the impact of an oxygen deficit on atheroma [30] have been recently extensively reviewed. Hypoxia via Hypoxia Inducible Factor (HIF) activation, has been proposed as one mechanism responsible for neo-angiogenesis [31].…”

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

“…Elevated levels of HIF-1α and HIF-2α are detected in human atherosclerotic carotid plaques compared with normal arteries, where HIF-1α colocalizes with CD68, a macrophage marker (116). Hypoxia has been implicated as a pathogenic factor in atherosclerosis and contributes to the proatherosclerotic functions of macrophages ( Figure 2A) (117). Several reports showed that lipid uptake and foam cell formation are dependent on hypoxia and HIF-1α (118)(119)(120).…”

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

“…Besides, glucose metabolism also differs between activation states (10): IFN-g or TLR ligands induce a shift from the liver type-PFK2 to the more active and ubiquitous PFK2, which triggers a subsequent increase in fructose-2,6-bisphosphate (11), whereas IL-4 promotes a higher lipid oxidation rate and an augmented use of the pentose phosphate pathway (12). Because glucose utilization is markedly changed under low oxygen tensions (hypoxia), the differences in glucose metabolism between the distinct macrophage polarization states correlate with the link between hypoxia and macrophage polarization observed in inflammatory pathologies where low tensions of oxygen are a common feature (13), as in atherosclerosis (14), cancer (15), and rheumatoid arthritis (16). In fact, macrophage functions acquired in response to LPS/IFN-g or IL-4 have been shown to be dependent on the hypoxia-inducible transcription factors HIF-1-or HIF-2, respectively (17).…”