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

Fangtian Fan, Fang Liu, Peiliang Shen, Li Tao, Hongjiang Zhang, Hongyan Wu

Clinical and experimental pharmacology & physiology 2023 Jan

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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. © 2022 John Wiley & Sons Australia, Ltd.

Citation

Fangtian Fan, Fang Liu, Peiliang Shen, Li Tao, Hongjiang Zhang, Hongyan Wu. Salvianolic acid B, a new type I IRE1 kinase inhibitor, abrogates AngII-induced angiogenesis by interacting with IRE1 in its active conformation. Clinical and experimental pharmacology & physiology. 2023 Jan;50(1):82-95