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

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.