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

Wenjun Zhang1,2, Mengwen Wang1,2, Kun Gao1,2

  • 1Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.

International Journal of Biological Sciences
|February 17, 2022
PubMed

Insights

Aortic dissection (AD) involves the IRE1α-XBP1s pathway in vascular smooth muscle cells. Inhibiting this pathway with MKC-3946 shows therapeutic potential for treating AD by reducing cell damage and apoptosis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Signaling

Background:

  • Aortic dissection (AD) is a life-threatening condition with significant long-term morbidity.
  • The role of the IRE1α-XBP1s signaling pathway in AD pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate the pharmacological targeting of the IRE1α-XBP1s pathway for AD treatment.
  • To evaluate the therapeutic potential of an IRE1α inhibitor in AD occurrence and progression.

Main Methods:

  • Western Blot and immunohistochemistry to analyze XBP1s expression in human AD samples.
  • In vitro studies using cultured vascular smooth muscle cells (VSMCs) treated with Angiotensin II (Ang II).
  • In vivo efficacy testing of the IRE1α inhibitor MKC-3946 in a mouse AD model.

Main Results:

  • XBP1s expression was significantly elevated in human AD tissues, specifically in VSMCs.
  • Ang II increased XBP1s expression and nuclear translocation in VSMCs, promoting ROS production, VSMC phenotypic switch, and apoptosis.
  • The IRE1α inhibitor MKC-3946 reversed these effects in vitro and in vivo, reducing XBP1s expression and protecting against AD.

Conclusions:

  • The IRE1α-XBP1s signaling pathway plays a critical role in the occurrence and progression of AD.
  • MKC-3946 demonstrates significant therapeutic potential for clinical application in treating aortic dissection.
Keywords:
Aortic dissectionApoptosisEndoplasmic Reticulum StressIRE1αReactive Oxygen SpeciesX-Box binding Protein 1

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