Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice
Background 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...
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PeerJ Inc.
2023-09-01
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| Online Access: | https://peerj.com/articles/16029.pdf |
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| author | Min Mao Yalan Deng Li Wang Gexin Zhao Ruomei Qi Huan Gong Tao Shen Yitian Xu Deping Liu Beidong Chen |
| author_facet | Min Mao Yalan Deng Li Wang Gexin Zhao Ruomei Qi Huan Gong Tao Shen Yitian Xu Deping Liu Beidong Chen |
| author_sort | Min Mao |
| collection | DOAJ |
| description | Background 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. Methods 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. Results 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 Pparg and its target genes (Slc2a4 (encodes for GLUT4), Adipoq, and Plin1) 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. Conclusions These findings indicated that CUMS induces adipose tissue dysfunction via 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 via which CUMS exacerbates atherosclerosis from the novel perspective of abnormal adipose function and identifies a novel potential therapeutic target for this disease. |
| first_indexed | 2024-03-09T06:53:31Z |
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| language | English |
| last_indexed | 2024-03-09T06:53:31Z |
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| spelling | doaj.art-cb97bcd1130149b699e23523f33c46562023-12-03T10:19:30ZengPeerJ Inc.PeerJ2167-83592023-09-0111e1602910.7717/peerj.16029Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- miceMin Mao0Yalan Deng1Li Wang2Gexin Zhao3Ruomei Qi4Huan Gong5Tao Shen6Yitian Xu7Deping Liu8Beidong Chen9The 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, ChinaThe 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, ChinaDepartment of Neurology, Beijing Hospital, Beijing, ChinaDepartment of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, United States of AmericaThe 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, ChinaThe 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, ChinaThe 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, ChinaBeijing Union University, Beijing, ChinaDepartment of Cardiology, Beijing Hospital, Beijing, ChinaThe 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, ChinaBackground 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. Methods 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. Results 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 Pparg and its target genes (Slc2a4 (encodes for GLUT4), Adipoq, and Plin1) 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. Conclusions These findings indicated that CUMS induces adipose tissue dysfunction via 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 via which CUMS exacerbates atherosclerosis from the novel perspective of abnormal adipose function and identifies a novel potential therapeutic target for this disease.https://peerj.com/articles/16029.pdfAdipose tissue dysfunctionCUMSAdipocyte hypertrophyAtherosclerosisInsulin resistance |
| spellingShingle | Min Mao Yalan Deng Li Wang Gexin Zhao Ruomei Qi Huan Gong Tao Shen Yitian Xu Deping Liu Beidong Chen Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice PeerJ Adipose tissue dysfunction CUMS Adipocyte hypertrophy Atherosclerosis Insulin resistance |
| title | Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice |
| title_full | Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice |
| title_fullStr | Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice |
| title_full_unstemmed | Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice |
| title_short | Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice |
| title_sort | chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in apoe mice |
| topic | Adipose tissue dysfunction CUMS Adipocyte hypertrophy Atherosclerosis Insulin resistance |
| url | https://peerj.com/articles/16029.pdf |
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