Cholesterol and HIF-1α: Dangerous Liaisons in Atherosclerosis

HIF-1 alpha exerts both detrimental and beneficial actions in atherosclerosis. While there is evidence that HIF-1 alpha could be pro-atherogenic within the atheromatous plaque, experimental models of atherosclerosis suggest a more complex role that depends on the cell type expressing HIF-1 alpha. In atheroma plaques, HIF-1 alpha is stabilized by local hypoxic conditions and by the lipid microenvironment. Macrophage exposure to oxidized LDLs (oxLDLs) or to necrotic plaque debris enriched with oxysterols induces HIF-1 alpha -dependent pathways. Moreover, HIF-1 alpha is involved in many oxLDL-induced effects in macrophages including inflammatory response, angiogenesis and metabolic reprogramming. OxLDLs activate toll-like receptor signaling pathways to promote HIF-1 alpha stabilization. OxLDLs and oxysterols also induce NADPH oxidases and reactive oxygen species production, which subsequently leads to HIF-1 alpha stabilization. Finally, recent investigations revealed that the activation of liver X receptor, an oxysterol nuclear receptor, results in an increase in HIF-1 alpha transcriptional activity. Reciprocally, HIF-1 alpha signaling promotes triglycerides and cholesterol accumulation in macrophages. Hypoxia and HIF-1 alpha increase the uptake of oxLDLs, promote cholesterol and triglyceride synthesis and decrease cholesterol efflux. In conclusion, the impact of HIF-1 alpha on cholesterol homeostasis within macrophages and the feedback activation of the inflammatory response by oxysterols via HIF-1 alpha could play a deleterious role in atherosclerosis. In this context, studies aimed at understanding the specific mechanisms leading to HIF-1 alpha activation within the plaque represents a promising field for research investigations and a path toward development of novel therapies.

Automated summary

HIF-1α plays a dual role in atherosclerosis, with both detrimental and beneficial effects. Its impact depends on the cell type expressing HIF-1α, and it can be stabilized by oxLDLs and oxysterols, leading to various responses including inflammation, angiogenesis, and metabolic reprogramming. Additionally, HIF-1α promotes the accumulation of cholesterol and triglycerides in macrophages.