The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China.
Department of Neurology, Beijing Hospital, Beijing, China.
PeerJ. 2023 Sep 4;11:e16029. doi: 10.7717/peerj.16029. eCollection 2023.
Chronic unpredictable mild stress (CUMS) has been shown to exacerbate atherosclerosis, but the underlying mechanism remains unknown. Adipose tissue is an energy storage organ and the largest endocrine organ in the human body, playing a key role in the development of cardiovascular disease. In this research, it was hypothesized that CUMS may exacerbate the development of atherosclerosis by inducing the hypertrophy and dysfunction of white adipocytes.
The CUMS-induced atherosclerosis model was developed in Western diet-fed apolipoprotein E (ApoE) mice. White adipose tissue (WAT), serum, aortic root, and the brachiocephalic trunk were collected and tested after 12 weeks of CUMS development. The mouse model of CUMS was evaluated for depression-like behavior using the open field test (OFT) and the elevated plus maze (EPM) test. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect serum noradrenaline and urine adrenaline protein levels. Serological assays were used to detect serum low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and free fatty acid (FFA) concentrations. Hematoxylin and eosin (H&E) staining and oil red O were used to detect atherosclerotic plaque area, lipid deposition, and adipocyte size. The mRNA levels of genes related to aberrant adipose tissue function were determined using real-time PCR. Immunofluorescence assay and western blotting were conducted to examine the expression of proteins in the adipose tissue samples.
CUMS aggravated vascular atherosclerotic lesions in ApoE mice. It decreased body weight while increasing the percentage of WAT. The serological results indicated that the concentration of HDL decreased in CUMS mice. Notably, adipocyte hypertrophy increased, whereas the mRNA levels of and its target genes ( (encodes for GLUT4), , and ) decreased. Further investigation revealed that CUMS increased subcutaneous inguinal WAT (iWAT) lipid synthesis and adipocyte inflammation while decreasing lipid hydrolysis and the expression of HDL-associated protein ApoA-I. Moreover, CUMS aggravated insulin resistance in mice and inhibited the insulin pathway in iWAT.
These findings indicated that CUMS induces adipose tissue dysfunction a mechanism that leads to dyslipidemia, increased inflammation, and insulin resistance in the body, thereby exacerbating atherosclerosis. Notably, CUMS that is involved in decreasing the expression of HDL-associated proteins in adipose tissue may be a crucial link between adipose hypertrophy and advanced atherosclerosis. This study reveals a novel mechanism which CUMS exacerbates atherosclerosis from the novel perspective of abnormal adipose function and identifies a novel potential therapeutic target for this disease.
慢性不可预测轻度应激（CUMS）已被证明会加重动脉粥样硬化，但潜在机制尚不清楚。脂肪组织是能量储存器官，也是人体最大的内分泌器官，在心血管疾病的发展中起着关键作用。在这项研究中，我们假设 CUMS 可能通过诱导白色脂肪细胞肥大和功能障碍来加重动脉粥样硬化的发展。
采用西方饮食喂养载脂蛋白 E（ApoE）小鼠建立 CUMS 诱导的动脉粥样硬化模型。在 CUMS 发展 12 周后收集和检测白色脂肪组织（WAT）、血清、主动脉根部和头臂干。采用旷场试验（OFT）和高架十字迷宫（EPM）试验评估 CUMS 小鼠的抑郁样行为。通过酶联免疫吸附试验（ELISA）检测血清去甲肾上腺素和尿肾上腺素蛋白水平。血清学检测用于检测血清低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、总胆固醇（TC）和游离脂肪酸（FFA）浓度。采用苏木精和伊红（H&E）染色和油红 O 检测动脉粥样硬化斑块面积、脂质沉积和脂肪细胞大小。实时 PCR 检测与异常脂肪组织功能相关的基因的 mRNA 水平。免疫荧光和 Western blot 检测脂肪组织样本中蛋白质的表达。
CUMS 加重了 ApoE 小鼠的血管动脉粥样硬化病变。CUMS 降低了体重，同时增加了 WAT 的百分比。血清学结果表明，CUMS 小鼠的 HDL 浓度降低。值得注意的是，脂肪细胞肥大增加，而 及其靶基因（编码 GLUT4）、 和 ）的 mRNA 水平降低。进一步研究表明，CUMS 增加了皮下腹股沟 WAT（iWAT）的脂质合成和脂肪细胞炎症，同时减少了脂质水解和 HDL 相关蛋白 ApoA-I 的表达。此外，CUMS 加重了小鼠的胰岛素抵抗并抑制了 iWAT 中的胰岛素途径。
这些发现表明，CUMS 诱导脂肪组织功能障碍，这是导致体内血脂异常、炎症增加和胰岛素抵抗的机制，从而加重动脉粥样硬化。值得注意的是，CUMS 下调脂肪组织中与 HDL 相关蛋白的表达可能是脂肪肥大与晚期动脉粥样硬化之间的关键联系。本研究从异常脂肪功能的新角度揭示了 CUMS 加重动脉粥样硬化的新机制，并确定了该疾病的一个新的潜在治疗靶点。
