Repetitive hypoxia increases lipid loading in human macrophages—a potentially atherogenic effect (original) (raw)
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2014
To gain insight into what biological role the methylation differences might contribute, the methylation data were functionally annotated, using Gene Ontology and the Human Protein Reference Database (www.hprd.org; Figure 2C), with subsequent Ingenuity Pathway Analysis to determine the biological pathways represented in the 75 unique hypermethylated genes and the 202 unique hypomethylated genes. The top pathway represented in the Ingenuity Pathway Analysis of the 75 hypermethylated genes was "cellular growth and proliferation," with 11 molecules represented (BMP7,
American Journal of Respiratory and Critical Care Medicine, 2002
Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free radicals and adhesion molecules were implicated in the pathogenesis of atherosclerosis leading to cardiovascular disorders. Therefore, we investigated the link between CD15, CD11c, CD11b, and CD64 expression on leukocytes and their ability to generate reactive oxygen species (ROS) in patients with OSA and control volunteers. We also studied the effects of hypoxia in vitro on monocytes from control subjects and the ability of monocytes from both groups to adhere to human endothelial cells in culture. The effect of nasal continuous positive airway pressure (nCPAP) treatment was studied as well. We found that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, increased intracellular ROS production in some monocyte and granulocyte subpopulations, and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects. Furthermore, nCPAP treatment was associated with downregulation of CD15 and CD11c monocyte expression and decreased basal ROS production in CD11c ϩ monocytes. Monocyte adherence to endothelial cells decreased as well. Our findings provide one of the possible mechanisms for explaining the high rate of cardiovascular morbidity in patients with sleep apnea.
Hypoxia Converts Human Macrophages Into Triglyceride-Loaded Foam Cells
Arteriosclerosis, Thrombosis, and Vascular Biology, 2006
Objectives-Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells. Methods and Results-Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in -oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl-coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of -oxidation, whereas the accumulation of triglycerides increased. Conclusions-The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.
Biochemistry (Moscow), 2019
Atherosclerosis is a chronic inflammatory disease associated with the formation of plaques in the arterial tunica intima. It is developed mainly in distorted arteries under hemodynamic shear stress [1]. Shear stress can be caused by a laminar or disturbed blood flow, with the lat ter leading to vessel damage and subsequent endothelium activation and thickening of tunica media and intima. Endotheliocytes trigger expression of adhesive agents, integrins, selectins, interleukins, interferons, and cytokines. Concurrent increase of vessel permeability leads to infiltration of the subendothelial space by low density lipoproteins (LDL). These molecules are bound in the intima by proteoglycans of the extracellular matrix and undergo various modifications like oxidation, prote olysis, etc. Modified LDL are absorbed by macrophages engaged during endothelium activation, which induces accumulation of intracellular cholesterol and leads to transformation of macrophages into foam cells [2]. Attraction of monocytes and thickening of intima by proliferation of smooth muscle cells leads to growth of atherosclerotic plaques and sparseness of capillaries that nourish the artery middle coat. An increased demand for oxygen triggers vascularization of the intima and plaque, but new vessels tend to originate at the perimeter of the plaque, with its center remaining under permanent hypoxia [3].
Sleep and Breathing, 2012
Purpose Obstructive sleep apnea (OSA) is a common disease which is associated with elevated inflammatory markers and adhesion molecules, possibly due to nightly intermittent hypoxia (IH). The purpose of this study was to test the hypothesis that IH would increase systemic inflammatory markers in healthy human males. Methods Healthy, young male subjects (n=9; 24±2 years) were exposed to a single daily isocapnic hypoxia exposure (oxyhemoglobin saturation=80%, 1 h/day) for 10 consecutive days. Serum granulocyte macrophage colonystimulating factor, interferon-γ, interleukin-1β, interleukin-6, interleukin-8, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 were measured before and following the 10 days of IH using Luminex.
Sleep, 2016
Increased visceral white adipose tissue (vWAT) mass results in infiltration of inflammatory macrophages that drive inflammation and insulin resistance. Patients with obstructive sleep apnea (OSA) suffer from increased prevalence of obesity, insulin resistance, and metabolic syndrome. Murine models of intermittent hypoxia (IH) mimicking moderate-severe OSA manifest insulin resistance following short-term IH. We examined in mice the effect of long-term IH on the inflammatory cellular changes within vWAT and the potential effect of normoxic recovery (IH-R). Methods: Male C57BL/6J mice were subjected to IH for 20 weeks, and a subset was allowed to recover in room air (RA) for 6 or 12 weeks (IH-R). Stromal vascular fraction was isolated from epididymal vWAT and mesenteric vWAT depots, and single-cell suspensions were prepared for flow cytometry analyses, reactive oxygen species (ROS), and metabolic assays. Results: IH reduced body weight and vWAT mass and IH-R resulted in catch-up weight and vWAT mass. IH-exposed vWAT exhibited increased macrophage counts (ATMs) that were only partially improved in IH-R. IH also caused a proinflammatory shift in ATMs (increased Ly6c (hi) (+) and CD36(+) ATMs). These changes were accompanied by increased vWAT insulin resistance with only partial improvements in IH-R. In addition, ATMs exhibited increased ROS production, altered metabolism, and changes in electron transport chain, which were only partially improved in IH-R. Conclusion: Prolonged exposures to IH during the sleep period induce pronounced vWAT inflammation and insulin resistance despite concomitant vWAT mass reductions. These changes are only partially reversible after 3 months of normoxic recovery. Thus, long-lasting OSA may preclude complete reversibility of metabolic changes.
Circulation, 2008
Background-Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results-Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP Ն4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP Ն4 hours daily. Conclusions-OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations. The online-only Data Supplement, which contains Methods and tables, can be found with this article at http://circ.ahajournals.org/cgi/content/ full/CIRCULATIONAHA.107.741512/DC1.