Insufficient BK channel function enhances NF-κB nuclear translocation and promotes IL-6 synthesis in vascular smooth muscle cells induced by AT1-AA.

The inflammatory phenotype of vascular smooth muscle cells (VSMCs) is an important factor in triggering vascular disease, and interleukin-6 (IL-6) is one of the earliest inflammatory cytokines upregulated in many inflammatory contexts. Angiotensin II-1 receptor autoantibody (AT1-AA) can promote the phenotypic transformation of VSMCs into macrophage-like cells, then synthesize abundant IL-6 to induce vascular inflammation. Previous studies suggested that abnormal BK channel function on the surface of VSMCs played an important role in the synthesis of IL-6, but the mechanism of abnormal BK channel involving in AT1-AA-induced IL-6 synthesis in VSMCs was unclear. In this study, the agonist NS1619 of the BK channel and the inhibitor Paxilline were used to reverse or exacerbate IL-6 synthesis in AT1-AA-induced VSMCs. It is known that NF-κB can enter the nucleus due to increased calcium ion concentration caused by BK channel dysfunction, thereby increasing IL-6 transcription. This study observed that Paxilline pretreatment significantly increased the residence time of AT1-AA-induced NF-κB in the nucleus, while NS1619 pretreatment showed the opposite trend. JSH-23 inhibiting NF-κB nuclear entry reversed the increase in IL-6 expression in VSMCs induced by AT1-AA. This study found that AT1-AA enhanced NF-κB nuclear translocation by inhibiting BK channel function, which in turn promoted IL-6 transcription in VSMCs, increased IL-6 synthesis and induced vascular inflammation. This study revealed the importance of BK channel dysfunction in the process of AT1-AA increasing IL-6 synthesis and promoting vascular inflammation, and provided a new idea for alleviating vascular inflammatory diseases from the perspective of improving potassium channel function.