Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Apr 15, 2021; 12(4): 466-479
Published online Apr 15, 2021. doi: 10.4239/wjd.v12.i4.466
Elevated retinol binding protein 4 levels are associated with atherosclerosis in diabetic rats via JAK2/STAT3 signaling pathway
Wan Zhou, Shan-Dong Ye, Wei Wang
Wan Zhou, Shan-Dong Ye, Wei Wang, Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Wan Zhou, Shan-Dong Ye, Wei Wang, Laboratory for Diabetes, Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Wan Zhou, Shan-Dong Ye, Wei Wang, Institute of Endocrinology and Metabolic Diseases, University of Science and Technology of China, Hefei 230001, Anhui Province, China
Author contributions: All authors contributed significantly to the study; Zhou W designed the research, analyzed the data, and wrote the manuscript; Ye SD and Wang W reviewed and edited the manuscript; Zhou W and Wang W are the guarantors of this work.
Supported by National Natural Science Foundation of China, No. 81800713 and No. 81971264; The Project of Natural Science Foundation of Anhui Province, No. 1808085QH292; and Fundamental Research Funds for the Central Universities, No. WK9110000041.
Institutional review board statement: The study was approved by The Ethics Committee of The First Affiliated Hospital of USTC. All procedures were performed in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments or comparable ethical standards.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of The First Affiliated Hospital of USTC (approval No. 20200049).
Conflict-of-interest statement: The authors have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article to declare.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei Wang, PhD, Chief Doctor, Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Hefei 230001, Anhui Province, China. hfww2001@ustc.edu.cn
Received: November 30, 2020
Peer-review started: November 30, 2020
First decision: January 25, 2021
Revised: February 3, 2021
Accepted: March 8, 2021
Article in press: March 8, 2021
Published online: April 15, 2021
Processing time: 129 Days and 21.8 Hours
Abstract
BACKGROUND

Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes, which results in an increased atherosclerotic burden, but the precise mechanisms for the occurrence and development of diabetic atherosclerosis have not been fully elucidated.

AIM

To summarize the potential role of retinol binding protein 4 (RBP4) in the pathogenesis of diabetic atherosclerosis, particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway.

METHODS

Male Wistar rats were randomly divided into three groups, including a control group (NC group), diabetic rat group (DM group), and diabetic atherosclerotic rat group (DA group). The contents of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), fasting insulin (FINS), fasting plasma glucose, and hemoglobin A1c (HbA1c) were measured. Moreover, the adipose and serum levels of RBP4, along with the expression levels of JAK2, phosphorylated JAK2 (p-JAK2), STAT3, phosphorylated STAT3 (p-STAT3), B-cell lymphoma-2 (Bcl-2), and Cyclin D1 in aortic tissues were also measured. Besides, homeostasis model assessment of insulin resistance (HOMA-IR) and atherogenic indexes (AI) were calculated.

RESULTS

Compared with the NC and DM groups, the levels LDL-c, TG, TC, FINS, HOMA-IR, RBP4, and AI were upregulated, whereas that of HDL-c was downregulated in the DA group (P < 0.05); the mRNA levels of JAK2, STAT3, Cyclin D1, and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group; P-JAK2, p-JAK2/JAK2 ratio, p-STAT3, p-STAT3/STAT3 ratio, Cyclin D1, and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group. In addition, as shown by Pearson analysis, serum RBP4 had a positive correlation with TG, TC, LDL-c, FINS, HbA1C, p-JAK2, p-STAT3, Bcl-2, Cyclin D1, AI, and HOMA-IR but a negative correlation with HDL-c. In addition, multivariable logistic regression analysis showed that serum RBP4, p-JAK2, p-STAT3, and LDL-c were predictors of the presence of diabetic atherosclerosis.

CONCLUSION

RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.

Keywords: Diabetes mellitus; Petinol binding protein 4; Atherosclerosis; JAK2/STAT3 signaling pathway; Cyclin D1

Core Tip: Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors including diabetes, which entails increased atherosclerotic burden, but the precise mechanisms for the occurrence and development of diabetic atherosclerosis are yet to be fully made clear. Retinol binding protein 4 is clinically associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases. This study aimed to explore the expression regulation and mechanism of retinol binding protein 4 that is involved in diabetic macrovascular disease in order to find therapeutic targets for diabetic macrovascular disease.