Wang Yue, Jiang Hong-Feng, Liu Bei-Bei, Chen Lei-Lei, Wang Yue, Liu Xin-Yan, Suo Min, Wu Xiao-Fan
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Key Laboratory of Remodeling-Related Cardiovascular Diseases of Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Front Cardiovasc Med. 2021 Oct 26;8:751519. doi: 10.3389/fcvm.2021.751519. eCollection 2021.
Obstructive sleep apnea is an atherogenesis factor of which chronic intermittent hypoxia is a prominent feature. Chronic intermittent hypoxia (CIH) exposure can sufficiently activate the sympathetic system, which acts on the β3 adrenergic receptors of brown adipose tissue (BAT). However, the activity of BAT and its function in CIH-induced atherosclerosis have not been fully elucidated. This study involved ApoE mice which were fed with a high-fat diet for 12 weeks and grouped into control and CIH group. During the last 8 weeks, mice in the CIH group were housed in cages to deliver CIH (12 h per day, cyclic inspiratory oxygen fraction 5-20.9%, 180 s cycle). Atherosclerotic plaques were evaluated by Oil Red O, hematoxylin and eosin, Masson staining, and immunohistochemistry. Afterward, we conducted immunohistochemistry, western blotting, and qRT-PCR of uncoupling protein 1 (UCP1) to investigate the activation of BAT. The level of serum total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and free fatty acid (FFA) were measured. Finally, RNA-Sequencing was deployed to explore the differentially expressed genes (DEGs) and their enriched pathways between control and CIH groups. Chronic intermittent hypoxia exposure promoted atherosclerotic plaque area with increasing CD68, α-SMA, and collagen in plaques. BAT activation was presented during CIH exposure with UCP1 up-regulated. Serum TC, triglyceride, LDL-c, and FFA were increased accompanied by BAT activation. HDL-c was decreased. Mechanistically, 43 lipolysis and lipid metabolism-associated mRNA showed different expression profiling between the groups. Calcium, MAPK, and adrenergic signaling pathway included the most gene number among the significantly enriched pathways. This study first demonstrated that BAT activation is involved in the progression of CIH-induced atherosclerosis, possibly by stimulating lipolysis.
阻塞性睡眠呼吸暂停是一种动脉粥样硬化形成因素，其突出特征是慢性间歇性缺氧。慢性间歇性缺氧（CIH）暴露可充分激活交感神经系统，该系统作用于棕色脂肪组织（BAT）的β3肾上腺素能受体。然而，BAT的活性及其在CIH诱导的动脉粥样硬化中的作用尚未完全阐明。本研究涉及用高脂饮食喂养12周的ApoE小鼠，并将其分为对照组和CIH组。在最后8周，CIH组的小鼠被置于笼子中以给予CIH（每天12小时，循环吸气氧分数5 - 20.9%，180秒循环）。通过油红O、苏木精和伊红、Masson染色以及免疫组织化学评估动脉粥样硬化斑块。之后，我们对解偶联蛋白1（UCP1）进行免疫组织化学、蛋白质免疫印迹和qRT-PCR，以研究BAT的激活情况。测量血清总胆固醇（TC）、甘油三酯、低密度脂蛋白胆固醇（LDL-c）、高密度脂蛋白胆固醇（HDL-c）和游离脂肪酸（FFA）水平。最后，采用RNA测序来探索对照组和CIH组之间的差异表达基因（DEG）及其富集途径。慢性间歇性缺氧暴露促进了动脉粥样硬化斑块面积增加，斑块中CD68、α-SMA和胶原蛋白增多。CIH暴露期间出现BAT激活，UCP1上调。血清TC、甘油三酯、LDL-c和FFA随着BAT激活而增加。HDL-c降低。机制上，43种脂解和脂质代谢相关的mRNA在两组之间表现出不同的表达谱。钙、MAPK和肾上腺素能信号通路在显著富集的通路中包含的基因数量最多。本研究首次证明BAT激活参与了CIH诱导的动脉粥样硬化进展，可能是通过刺激脂解作用。
