AGEs-RAGE axis causes endothelial-to-mesenchymal transition in early calcific aortic valve disease via TGF-β1 and BMPR2 signaling

Guorong Deng; Liyi Zhang; Chunliang Wang; Shuang Wang; Jiacheng Xu; Jing Dong; Qi Kang; Xia Zhai; Yun Zhao; Zhonggui Shan

doi:10.1016/j.exger.2020.111088

AGEs-RAGE axis causes endothelial-to-mesenchymal transition in early calcific aortic valve disease via TGF-β1 and BMPR2 signaling

Exp Gerontol. 2020 Nov:141:111088. doi: 10.1016/j.exger.2020.111088. Epub 2020 Sep 7.

Authors

Guorong Deng¹, Liyi Zhang², Chunliang Wang³, Shuang Wang⁴, Jiacheng Xu³, Jing Dong⁵, Qi Kang⁵, Xia Zhai⁵, Yun Zhao⁵, Zhonggui Shan⁶

Affiliations

¹ Department of Cardiac Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China; Department of Cardiology, The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang 712000, China; The Shaanxi Key Laboratory of Integrated Traditional and Western Medicine for the Prevention and Treatment of Cardiovascular Diseases, Shaanxi University of Chinese Medicine, Xi'an 712046, China.
² Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen 361101, China.
³ Department of Cardiac Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
⁴ Department of Orthopedics, Shangnan County Hospital, Shangluo 726300, China.
⁵ Department of Cardiology, The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang 712000, China; The Shaanxi Key Laboratory of Integrated Traditional and Western Medicine for the Prevention and Treatment of Cardiovascular Diseases, Shaanxi University of Chinese Medicine, Xi'an 712046, China.
⁶ Department of Cardiac Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China; Department of Clinical Medicine, Fujian Medical University, Fuzhou 350100, China. Electronic address: szgdoctor@outlook.com.

PMID: 32911032
DOI: 10.1016/j.exger.2020.111088

Abstract

Recent studies reported that advanced glycation end products (AGEs) and endothelial-to-mesenchymal transition (EndMT) were involved in the calcific aortic valve disease (CAVD). However, the roles of AGEs in EndMT in the development of CAVD have not been elucidated. In this study, six-week-old male Apoe^-/- mice were divided into four groups based on the following feeding periods: 0, 2, 4, and 6 months. The latter three groups were further divided into three subgroups corresponding to the following diet treatments: normal diet, high-fat diet + normal saline injection, and high-fat diet + aminoguanidine injection. Weight gain was monitored weekly. Finally, heart echocardiographic assessments were performed, and serum lipid levels, the protein expression and the histological changes in the aortic valves were determined. Results showed that the AGE inhibitor aminoguanidine alleviated the transaortic valve velocity and decreased the total cholesterol and low-density lipoprotein cholesterol levels. Calcification and carboxymethyl-lysine deposition were firstly detected around the aortic valve surfaces, whereas aminoguanidine injection attenuated their accumulation. In the early stage, HFD-activated AGEs-RAGE signaling resulted in the alpha-smooth muscle actin (α-SMA) upregulation and the vascular endothelium cadherin (VE-cadherin) downregulation on the valve endothelial layer. The activation resulted in early the transforming growth factor-β1 (TGF-β1) and the alkaline phosphatase (ALP) upregulation, and simultaneously reduced the bone morphogenetic protein receptor type II (BMPR2) expression. However, aminoguanidine restricted these proteins changes by inhibiting the interaction of AGEs and RAGE. In addition, immunofluorescence images showed obvious double-positive staining of ALP and α-SMA on the valve surfaces, revealing the contribution of EndMT to the early calcification. Therefore, this study demonstrates that activation of the AGEs-RAGE axis induced EndMT, promoting the progression of the aortic valve calcification in the initial stage via the counteraction of BMPR2 and TGF-β1 signaling.

Keywords: Advanced glycation end products; Calcific aortic valve disease; Endothelial to mesenchymal transition; Valve endothelial cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aortic Valve Disease*
Aortic Valve*
Bone Morphogenetic Protein Receptors, Type II
Cells, Cultured
Male
Mice
Transforming Growth Factor beta1

Substances

Transforming Growth Factor beta1
Bone Morphogenetic Protein Receptors, Type II