Pharmacologic IRE1α kinase inhibition alleviates aortic dissection by decreasing vascular smooth muscle cells apoptosis

Wenjun Zhang; Mengwen Wang; Kun Gao; Xiaodan Zhong; Yang Xie; Lei Dai; Wanjun Liu; Yujian Liu; Xingwei He; Shiliang Li; Thati Madhusudhan; Hongjie Wang; Hesong Zeng

doi:10.7150/ijbs.63593

Pharmacologic IRE1α kinase inhibition alleviates aortic dissection by decreasing vascular smooth muscle cells apoptosis

Int J Biol Sci. 2022 Jan 1;18(3):1053-1064. doi: 10.7150/ijbs.63593. eCollection 2022.

Authors

Wenjun Zhang^{1

2}, Mengwen Wang^{1

2}, Kun Gao^{1

2}, Xiaodan Zhong^{1

2}, Yang Xie^{1

2}, Lei Dai^{1

2}, Wanjun Liu^{1

2}, Yujian Liu^{1

2}, Xingwei He^{1

2}, Shiliang Li³, Thati Madhusudhan⁴, Hongjie Wang^{1

2}, Hesong Zeng^{1

2}

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
² Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, PR China.
³ Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁴ Center for Thrombosis and Hemostasis, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Abstract

Aortic dissection (AD) is a rare but catastrophic disorder, and associated with significant morbidity among survivors. This study aimed to target IRE1α-XBP1s pathway pharmacologically, and evaluate its therapeutic potential in the occurrence and progression of AD. Western Blot and immunohistochemistry results showed that expression of XBP1s was significantly increased in the human aorta samples of AD group in compared with the control group, and exclusively in aortic vascular smooth muscle cells (VSMCs). Further in vitro study revealed that Angiotensin II (Ang II) could increase the expression of XBP1s and promote its nuclear translocation in cultured VSMCs, which leads to numerous gene transcription, including gp91phox, Chop, Cleaved-caspase 3, Bax, and Bcl-2. These genes contribute to the production of reactive oxygen species (ROS), VMSCs phenotypic switch and apoptosis. Whereas an IRE1α endoribonuclease domain inhibitor MKC-3946 could reverse it. Finally, the efficacy of MKC-3946 was tested in a mouse AD model. As shown in vitro, MKC-3946 could reduce the expression of XBP1s and protect against AD by suppressing XBP1s associated ROS production and apoptosis in VSMCs in vivo. The current study revealed the relevant role of IRE1α-XBP1s signaling pathway in AD occurrence and progression. MKC-3946 could be of great potential in clinical application.

Keywords: Aortic dissection; Apoptosis; Endoplasmic Reticulum Stress; IRE1α; Reactive Oxygen Species; X-Box binding Protein 1.

Publication types

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

MeSH terms

Animals
Aortic Dissection*
Apoptosis / genetics
Endoplasmic Reticulum Stress
Endoribonucleases* / genetics
Endoribonucleases* / metabolism
Mice
Muscle, Smooth, Vascular / metabolism
Myocytes, Smooth Muscle / metabolism
Protein Serine-Threonine Kinases / genetics
Reactive Oxygen Species
X-Box Binding Protein 1

Substances

Reactive Oxygen Species
X-Box Binding Protein 1
Xbp1 protein, mouse
Ern1 protein, mouse
Protein Serine-Threonine Kinases
Endoribonucleases