Pharmacological inhibition of STAT3 by BP‐1‐102 inhibits intracranial aneurysm formation and rupture in mice through modulating inflammatory response

Abstract

As an inhibitor of STAT3, BP‐1‐102 can regulate the inflammation response caused by vascular smooth muscle cells (VSMCs) by inhibiting the JAK/STAT3/NF‐κB pathway, thereby attenuating the symptoms of intracranial aneurysm (IA). IA mouse model was established by stereotactic injection of elastase to evaluate the effect of BP‐1‐102. The expression levels of smooth muscle markers and matrix metalloproteinases (MMPs) were detected by qRT‐PCR, and the levels of inflammatory factors were detected by ELISA and qRT‐PCR. The protein levels of the NF‐κB signaling pathway factors were examined by Western blot. BP‐1‐102 reduced blood pressure in aneurysm mice, up‐regulated smooth muscle cell markers MHC, SMA, and SM22, and down‐regulated the expression of MMP2 and MMP9 in vascular tissues. At the same time, BP‐1‐102 also down‐regulated the expression levels of inflammatory response factors and the NF‐κB pathway proteins. In the IA model, BP‐1‐102 can reduce the expression of inflammatory factors and MMPs bound to NF‐κB by inhibiting the activation of the JAK/STAT3/NF‐κB pathway proteins, and then restore the vascular wall elastin to reduce blood pressure, thereby treating aneurysm.

The Role of NF-κB in Intracranial Aneurysm Pathogenesis: A Systematic Review

“…In addition to that, polymorphism in the genotype of the NF-κB promoter was linked to a lower risk of IAs [ 17 ]. Similar to clinical studies, experimental studies using different animal models showed the elevated mRNA expression, protein levels, and/or activation of NF-κB in IA tissue compared to normal control arteries ( Table 2 ) [ 8 , 20 , 23 , 25 , 26 , 27 , 29 , 30 , 31 , 32 , 33 , 34 , 40 , 43 ]. The animal experimental studies revealed that blocking NF-κB P50 expression and NF-κB activation reduced the incidence of IA formation ( Table 3 ) [ 8 , 40 ], while enhanced NF-κB activation was linked to increased IA formation ( Table 3 ) [ 11 ].…”

Dexmedetomidine alleviates inflammatory response and oxidative stress injury of vascular smooth muscle cell via α2AR/GSK-3β/MKP-1/NRF2 axis in intracranial aneurysm

“…The mortality rate of IA-induced SAH is 50% worldwide. The living quality of only 30%-45% survivors returns to their pre-onset state [ 4 ]. History of hypertension, genetics, sex, age, and cigarette smoking are potential contributors of aneurysm rupture [ 5 ].…”

BP‑1‑102 exerts antitumor effects on T‑cell acute lymphoblastic leukemia cells by suppressing the JAK2/STAT3/c‑Myc signaling pathway

“…Zhixian Jiang et al . demonstrated that BP-1-102 suppressed the JAK/STAT3/NF-κB pathway in intracranial aneurysms, reduced the vascular inflammatory response, alleviated the symptoms of intracranial aneurysms and prevented their rupture ( 39 , 40 ).…”

“…Qi-Ying Wu et al demonstrated that BP-1-102 inhibited JAK2/STAT3/NF-κB pathway activation in a mouse abdominal aortic aneurysm model, thereby reducing the expression of proinflammatory cytokines, decreasing inflammatory cell infiltration, and ultimately impeding the development and progression of abdominal aortic aneurysms (38). Zhixian Jiang et al demonstrated that BP-1-102 suppressed the JAK/STAT3/NF-κB pathway in intracranial aneurysms, reduced the vascular inflammatory response, alleviated the symptoms of intracranial aneurysms and prevented their rupture (39,40).…”