Activation of BK channels ameliorates cardiac injury Via NFκB-NLRP3 signaling in angiotensin II-induced hypertension mouse model.

BACKGROUND

Hypertension-induced cardiac fibrosis leads to heart failure. Large-conductance calcium-activated potassium (BK) channels regulate vascular tone, and their activation may mitigate fibrosis. This study explores the impact of BK channel activation on angiotensin II (Ang II)-induced hypertension and cardiac fibrosis and its effects on nuclear factor-kappa B (NFκB) signaling.

METHODS

Male C57BL/6 J mice were infused with Ang II for 4 weeks to induce hypertension and cardiac fibrosis. The BK channel activator BMS-191011 was administered via intraperitoneal injection. Cardiac tissue was analyzed using histology, Western blotting and qPCR. Single channel recordings were used to analyze the activation of BKα channels. A dihydroethidium (DHE) Assay was used to detect superoxide (ROS) production. Superoxide Dismutase (SOD) was measured using a colorimetric activity kit. In vitro, macrophages (RAW 264.7) were stimulated with Ang II, to detect NFκB activation and macrophage polarization.

RESULTS

The expression of BKα mRNA and protein abundance was decreased while markers of cardiac fibrosis (fibronectin, vimentin, αSMA and TGF-β) and ROS production were increased in the hearts of Ang II-induced hypertensive mice. In addition, macrophage infiltration was significantly increased along with inflammatory cytokines IFNγ, IL-6, IL-4, IL-10 and TNFα. The BK channel opener, BMS-191011, significantly reduced hypertension, cardiac fibrosis, and ROS production, but restored SOD in the hearts of Ang II-treated mice. In cultured macrophages, we found that Ang II increased inflammatory cytokines through NFκB-NLRP3-caspase-1 signaling. After Ang II treatment, BK channel activation inhibited NFκB, NLRP3 and caspase-1 expression. BK channel activation also suppressed NFκB-NLRP3 signaling, leading to reduced ROS accumulation and restored SOD activity.

CONCLUSION

BK channel activation reduces Ang II-induced hypertension and cardiac fibrosis by modulating oxidative stress, inflammation and macrophage polarization through the NFκB-NLRP3 pathway. These findings implicate BK channel activators as a potential novel therapeutic strategy for hypertensive cardiomyopathy.