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
ARTICLE HIGHLIGHTS
Research background

With the increasing incidence of diabetes, the incidence of diabetic macroangiopathy continues to rise, which entails and increases atherosclerotic burden. Retinol binding protein 4 (RBP4) is clinically associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases. However, the precise role of RBP4 in the initiation and progression of atherosclerosis remains elusive.

Research motivation

We tried to provide new insight into the mechanism of diabetic atherosclerosis.

Research objectives

This study aimed to explore the expression regulation and mechanism of RBP4 in the diabetic rats with atherosclerosis, and to examine whether the role of RBP4 in the progression of atherosclerosis is mediated via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway.

Research methods

Male Wistar rats were randomly divided into a control group (NC group), diabetic rats (DM group), and diabetic atherosclerosis rats (DA group). At the end of week 19, serum RBP4, fasting insulin (FINS), fasting plasma glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and hemoglobin A1c were measured. Except for hematoxylin and eosin staining and immunohistochemistry, the thoracic aorta was separated and extracted for mRNA and Western blot assay of JAK2, phosphorylated-JAK2 (p-JAK2), STAT3, phosphorylated-STAT3 (p-STAT3), Cyclin D1, and B-cell lymphoma-2 (Bcl-2). In addition, visceral adipose tissue was extracted for the measurement of RBP4 mRNA and the quantitative protein expression of RBP4. Homeostasis model assessment of insulin resistance (HOMA-IR) and atherogenic index (AI) were calculated.

Research results

Compared with the NC group and DM group, the levels of LDL-c, TG, TC, FINS, HOMA-IR, RBP4, and AI increased, while the level of HDL-c decreased in the DA group. The mRNA expression of JAK2, STAT3, Cyclin D1, and Bcl-2 in the DA group was significantly increased compared with the NC group and DM group. P-JAK2, p-JAK2/JAK2 ratio, p-STAT3, p-STAT3/STAT3 ratio, Cyclin D1, and Bcl-2 in the DA group were significantly increased at protein levels compared with the NC group and DM group. Pearson analysis showed that serum RBP4 was positively correlated with TG, TC, LDL-c, FINS, hemoglobin A1c, p-JAK2, p-STAT3, Bcl-2, CyclinD1, AI, and HOMA-IR but negatively correlated 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.

Research conclusions

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

Research perspectives

These results provide important insights into the mechanism of diabetic atherosclerosis and may help find therapeutic targets for diabetic macrovascular disease.