Chronic Intermittent Hypoxia Exposure Induces Atherosclerosis in ApoE Knockout Mice

Fang, Guoqiang; Song, Dongmei; Ye, Xiaobing; Mao, Sun‐Zhong; Liu, Gang; Liu, Shu Fang

doi:10.1016/j.ajpath.2012.07.024

Cited by 41 publications

(33 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanisms by which CIH accelerates atherosclerotic disease are unclear but may include hypertension, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress (6). In rodent models, CIH accelerates the progression of atherosclerosis in C57BL/6J mice on a high-cholesterol diet (9,10) and in ApoE-deficient mice (11,12) by inducing dyslipidemia (10) and systemic inflammation (11,(13)(14)(15).…”

Section: Measurements and Main Resultsmentioning

confidence: 99%

Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Drager

Yao

Hernandez

et al. 2013

Am J Respir Crit Care Med

151

120

View full text Add to dashboard Cite

Section: Measurements and Main Resultsmentioning

confidence: 99%

Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Drager

Yao

Hernandez

et al. 2013

Am J Respir Crit Care Med

151

120

View full text Add to dashboard Cite

“…Atherosclerosis is a well-known inflammation and lipid-associated disease, and chronic intermittent hypoxia (CIH) exacerbates disease progression (6,7,54). An important mechanism that contributes to atherosclerosis is recruitment of macrophages that scavenge fatty acids, resulting in the formation of foam cells.…”

Section: Hif-2␣ Regulates Cholesterol Homeostasismentioning

confidence: 99%

“…In chronic hypoxic diseases, such as in patients with obstructive sleep apnea, no change or an increase in serum and liver cholesterol levels are observed, which can be reversed by continuous positive airway pressure (3)(4)(5). Moreover, mice exposed to chronic intermittent hypoxia (CIH) have a significant increase in total cholesterol levels (6,7). These studies suggest that hypoxiasignaling pathways activate an adaptive response important in cholesterol homeostasis.…”

mentioning

confidence: 99%

Loss of von Hippel-Lindau Protein (VHL) Increases Systemic Cholesterol Levels through Targeting Hypoxia-Inducible Factor 2α and Regulation of Bile Acid Homeostasis

Ramakrishnan

Taylor

et al. 2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

Cholesterol synthesis is a highly oxygen-dependent process. Paradoxically, hypoxia is correlated with an increase in cellular and systemic cholesterol levels and risk of cardiovascular diseases. The mechanism for the increase in cholesterol during hypoxia is unclear. Hypoxia signaling is mediated through hypoxia-inducible factor 1␣ (HIF-1␣) and HIF-2␣. The present study demonstrates that activation of HIF signaling in the liver increases hepatic and systemic cholesterol levels due to a decrease in the expression of cholesterol hydroxylase CYP7A1 and other enzymes involved in bile acid synthesis. Specifically, activation of hepatic HIF-2␣ (but not HIF-1␣) led to hypercholesterolemia. HIF-2␣ repressed the circadian expression of Rev-erb␣, resulting in increased expression of E4BP4, a negative regulator of Cyp7a1. To understand if HIF-mediated decrease in bile acid synthesis is a physiologically relevant pathway by which hypoxia maintains or increases systemic cholesterol levels, two hypoxic mouse models were assessed, an acute lung injury model and mice exposed to 10% O 2 for 3 weeks. In both models, cholesterol levels increased with a concomitant decrease in expression of genes involved in bile acid synthesis. The present study demonstrates that hypoxic activation of hepatic HIF-2␣ leads to an adaptive increase in cholesterol levels through inhibition of bile acid synthesis. Cholesterol is an essential nutrient important in many metabolic processes, and its levels are tightly regulated. Cholesterol synthesis is a highly oxygen-dependent process. The final step from lanosterol to cholesterol conversion requires nine molecules of dioxygen (1). However, systemic hypoxia is associated with an increase in cholesterol levels. Individuals living at high altitude are at high risk for coronary heart disease due to elevated low-density lipoprotein and total cholesterol levels caused by high-altitude hypoxia (2). In chronic hypoxic diseases, such as in patients with obstructive sleep apnea, no change or an increase in serum and liver cholesterol levels are observed, which can be reversed by continuous positive airway pressure (3-5). Moreover, mice exposed to chronic intermittent hypoxia (CIH) have a significant increase in total cholesterol levels (6, 7). These studies suggest that hypoxiasignaling pathways activate an adaptive response important in cholesterol homeostasis. Several mechanisms were proposed to account for hypoxia-induced dyslipidemia (8, 9). However, the mechanisms by which hypoxia regulates cholesterol homeostasis are not clear. Hypoxic signaling is mediated by an oxygen-sensitive transcription factor, hypoxia-inducible factor (HIF), consisting of two isoforms, HIF-1␣ and HIF-2␣ (10). Activation of HIF-1␣ induces glycolytic genes, whereas activation of HIF-2␣ regulates the expression of genes that are involved in fatty acid synthesis, fatty acid uptake, inflammation, fibrosis, and vascular tumors (9,(11)(12)(13)(14).In this study, liver hypoxia-induced dyslipidemia was shown to be associated with spontaneou...

show abstract

“…IHR is an independent risk factor for the development of coronary and cerebral vascular diseases, two common consequences of atherosclerosis (1)(2)(3). The mechanisms by which hypoxic signaling accelerates the initiation and progression of atherosclerosis have yet to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Propofol selectively inhibits nuclear factor-κB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation

Zhang

2014

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Intermittent hypoxia/reoxygenation (IHR) induces proinflammatory cytokines, contributing to the pathogenic process of atherosclerosis associated with obstructive sleep apnea (OSA). Two transcription factors, nuclear factor-κB (NF-κB) and hypoxia-inducible factor-1 (HIF-1), have been indicated to mediate proinflammatory cytokines during IHR. The anti-inflammatory effects of propofol have attracted increasing attention in regard to the treament of multiple diseases associated with inflammation. The present study examined whether propofol inhibits NF-κB and HIF-1 activity in vascular endothelial cells during IHR. EA.hy926 endothelial cells were exposed to IHR for 64 cycles with or without propofol treatment. Gene knockdown by transfection of siRNA against p38 mitogen-activated protein kinase (MAPK) was also used to investigate the molecular mechanisms. Compared with the control group, IHR exposure significantly induced the activation of NF-κB and HIF-1, enhanced the mRNA expression of proinflammatory cytokines and increased the activation of p38 MAPK. Propofol dose-dependently inhibited the IHR-induced activation of NF-κB, but did not change the activation of HIF-1, which was accompanied by decreased levels of proinflammatory cytokines. In addition, IHR-induced p38 MAPK activity was attenuated by propofol in a similar manner to the reduction in NF-κB activity. Furthermore, knockdown of p38 MAPK with siRNA significantly reduced the IHR-induced activation of NF-κB, while not affecting HIF-1. These data demonstrate that propofol selectively attenuates the IHR-induced activation of NF-κB, but not HIF-1, in vascular endothelial cells, and these beneficial effects are likely to be based on the inhibition of the p38 MAPK signaling pathway. Propofol may have the potential to prevent atherosclerosis in patients with OSA by inhibiting NF-κB-mediated inflammation in the vascular endothelium.

show abstract

Chronic Intermittent Hypoxia Exposure Induces Atherosclerosis in ApoE Knockout Mice

Cited by 41 publications

References 48 publications

Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Loss of von Hippel-Lindau Protein (VHL) Increases Systemic Cholesterol Levels through Targeting Hypoxia-Inducible Factor 2α and Regulation of Bile Acid Homeostasis

Propofol selectively inhibits nuclear factor-κB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation

Contact Info

Product

Resources

About