Published online Apr 15, 2021. doi: 10.4239/wjd.v12.i4.466
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
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.
We tried to provide new insight into the mechanism of diabetic atherosclerosis.
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.
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.
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.
The current study demonstrated that RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.
These results provide important insights into the mechanism of diabetic atherosclerosis and may help find therapeutic targets for diabetic macrovascular disease.