Salvianolic acid B, a new type I IRE1 kinase inhibitor, abrogates AngII-induced angiogenesis by interacting with IRE1 in its active conformation

Clin Exp Pharmacol Physiol. 2023 Jan;50(1):82-95. doi: 10.1111/1440-1681.13726. Epub 2022 Oct 11.

Abstract

Angiotensin II (AngII)-mediated pathological angiogenesis is one of the important factors promoting the progression of atherosclerosis, tumour metastasis, and diabetic retinopathy. Here, we first demonstrate that salvianolic acid B (Sal B) attenuated AngII-induced angiogenesis by downregulating the IRE1/ASK1/JNK/p38MAPK signalling pathway and protected vascular endothelial cells from hypoxia-induced damage. These pharmacological consequences could be ascribed to the unique interactions between Sal B and the ATP-binding cavity of IREIα, leading to bi-directional roles of IRE1 kinase and endonuclease activity; this may possibly be one of the essential mechanisms of the bi-directional regulation of angiogenesis in different conditions. Moreover, our results indicated that IRE1 was a novel anti-angiogenesis target and type I IRE1 kinase inhibitor (e.g., Sal B, APY29) and might be a potentially eligible low-toxicity drug for treating AngII-mediated pathological angiogenesis.

Keywords: AngII; angiogenesis; salvianolic acid B; type I IRE1 kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Endothelial Cells / drug effects
  • Neovascularization, Pathologic* / drug therapy
  • Neovascularization, Pathologic* / metabolism
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism

Substances

  • Angiotensin II
  • salvianolic acid B
  • Protein Kinase Inhibitors
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases