Abstract
Obstructive sleep apnea (OSA) affects 8–10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities. In CIH-exposed mice, closely mimicking the chronicity of human OSA, increased accumulation and proliferation of pro-inflammatory metabolic M1-like macrophages highly expressing CD36, emerged in aorta. Transcriptomic and MeDIP-seq approaches identified activation of pro-atherogenic pathways involving a complex interplay of histone modifications in functionally-relevant biological pathways, such as inflammation and oxidative stress in aorta macrophages. Discontinuation of CIH did not elicit significant improvements in aorta wall macrophage phenotype. However, CIH-induced aorta changes were absent in CD36 knockout mice, Our results provide mechanistic insights showing that CIH exposures during sleep in absence of concurrent pro-atherogenic settings (i.e., genetic propensity or dietary manipulation) lead to the recruitment of CD36(+)high macrophages to the aortic wall and trigger atherogenesis. Furthermore, long-term CIH-induced changes may not be reversible with usual OSA treatment.
Highlights
Obstructive sleep apnea (OSA) affects 8–10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities
To further confirm the notion that bone-marrow recruitment provides a major source of increased macrophage accumulation in aorta wall following CIH exposures, we isolated bone-marrow monocytes from RFP mice and injected into RA- or CIH-exposed WT C57BL/6 J mice
This study shows that prolonged chronic exposures to intermittent hypoxia during sleep mimicking OSA elicit recruitment of bone marrow derived macrophages to the aortic wall even when the underlying exposures occur in the absence of a concurrent pro-atherogenic setting, such as genetic propensity or altered dietary intake
Summary
Obstructive sleep apnea (OSA) affects 8–10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities. In CIH-exposed mice, closely mimicking the chronicity of human OSA, increased accumulation and proliferation of pro-inflammatory metabolic M1-like macrophages highly expressing CD36, emerged in aorta. Chronic intermittent hypoxia (CIH) during the sleep period, has been used as a useful murine model of OSA, and promotes the presence of increased atherogenesis, in conjunction with other predisposing risk factors such as transgenic ablation of LdlR or ApoE, or concurrent feeding of a high fat diet[8,9,10,11,12,13,14]. Through multi-omic approaches we show that the increased accumulation and proliferation of pro-inflammatory M1-like macrophages in the murine aorta is characterized by a set of differentially expressed protein surface markers, global transcriptional changes and corresponding epigenetic modifications in these cells. We examined the effect of treatment, i.e., cessation of CIH, on the reversibility of the morphological and macrophage changes
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