A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy

• Published in: Cell death & disease Vol. 11; no. 2; p. 131
• Main Authors: Wu, Qi-ying, Cheng, Zhao, Zhou, Yang-zhao, Zhao, Yuan, Li, Jian-ming, Zhou, Xin-min, Peng, Hong-ling, Zhang, Guang-sheng, Liao, Xiao-bo, Fu, Xian-ming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.02.2020; Springer Nature B.V
• Subjects: 13/2; 13/31; 13/51; 631/250/256/2515; 692/699/75/593/1301; Aminosalicylic Acids - pharmacology; Aneurysms; Angiotensin; Angiotensin II; Animals; Antibodies; Aorta, Abdominal - drug effects; Aorta, Abdominal - metabolism; Aorta, Abdominal - pathology; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Aortic Aneurysm, Abdominal - prevention & control; Aortic aneurysms; Aortitis - chemically induced; Aortitis - metabolism; Aortitis - pathology; Aortitis - prevention & control; Apolipoprotein E; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Autophagy-Related Proteins - metabolism; Bcl-x protein; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cells, Cultured; Cytokines; Disease Models, Animal; Elastin; Immunology; Inflammation; Janus kinase 2; Janus Kinase 2 - metabolism; Life Sciences; Male; Mice, Knockout, ApoE; NF-kappa B - metabolism; NF-κB protein; Oral administration; Phagocytosis; Phosphorylation; Signal Transduction; Smooth muscle; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Sulfonamides - pharmacology; Vascular Remodeling - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2326-2

Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced AAA in ApoE −/− mice were investigated. AAA was induced in ApoE −/− mice with infusion of AngII for 28 days. BP-1-102 was administrated orally to mice every other day. Mice were sacrificed on day 7, day 14, and day 28 to evaluate the treatment effects. BP-1-102 markedly decreased AAA incidence and aortic diameter, maintained elastin structure and volume, reduced the expression of pro-inflammatory cytokines and MMPs, and inhibited inflammatory cells infiltration. Moreover, BP-1-102 dramatically reduced the expression of JAK2, p-STAT3, p-NF-κB, and Bcl-xL but maintained the expression of LC3B and Beclin in AAA tissues. In vitro, vascular smooth muscle cells (VSMCs) were treated with AngII and/or BP-1-102 at indicated time and concentration. BP-1-102 inhibited AngII-induced JAK2/STAT3 and NF-κB signaling activation and maintained autophagy-related proteins expression in VSMCs. Taken together, our findings suggest that BP-1-102 inhibits vascular inflammation and AAA progression through decreasing JAK2/STAT3 and NF-κB activation and maintaining autophagy.