Kv1.5 channel mediates monosodium urate-induced activation of NLRP3 inflammasome in macrophages and arrhythmogenic effects of urate on cardiomyocytes

• Published in: Molecular biology reports Vol. 49; no. 7; pp. 5939 - 5952
• Main Authors: Li, Peili, Kurata, Yasutaka, Taufiq, Fikri, Kuwabara, Masanari, Ninomiya, Haruaki, Higaki, Katsumi, Tsuneto, Motokazu, Shirayoshi, Yasuaki, Lanaspa, Miguel A., Hisatome, Ichiro
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.07.2022; Springer Nature B.V
• Subjects: Action potential; Animal Anatomy; Animal Biochemistry; Animals; Atrial Remodeling; Biomedical and Life Sciences; Cardiac arrhythmia; Cardiomyocytes; Caspase 1 - metabolism; Caspase-1; Cell activation; Fibrillation; Gout; Gout - drug therapy; Gout - metabolism; Gout - pathology; Heat shock; Histology; Hsp70 protein; Humans; IL-1β; Inflammasomes; Inflammasomes - metabolism; Interleukin-1beta - genetics; Kv1.5 Potassium Channel - metabolism; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - metabolism; Mice; Molecular biology; Morphology; Myocytes; Myocytes, Cardiac - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Original; Original Article; Phosphine; Plasma; Potassium channels (voltage-gated); Proteins; Rheumatism; siRNA; Uric acid; Uric Acid - metabolism; Uric Acid - pharmacology; Atrial myocytes; Monosodium urate; Kv1.5; NLRP3 inflammasome
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-022-07378-1

Background Gout is usually found in patients with atrial fibrillation (AF). K+ efflux is a common trigger of NLRP3 inflammasome activation which is involved in the pathogenesis of AF. We investigated the role of the K+ channel Kv1.5 in monosodium urate crystal (MSU)-induced activation of the NLRP3 inflammasome and electrical remodeling in mouse and human macrophages J774.1 and THP-1, and mouse atrial myocytes HL-1. Methods and Results Macrophages, primed with lipopolysaccharide (LPS), were stimulated by MSU. HL-1 cells were incubated with the conditioned medium (CM) from MSU-stimulated macrophages. Western blot, ELISA and patch clamp were used. MSU induced caspase-1 expression in LPS-primed J774.1 cells and IL-1β secretion, suggesting NLRP3 inflammasome activation. A selective Kv1.5 inhibitor, diphenyl phosphine oxide-1 (DPO-1), and siRNAs against Kv1.5 suppressed the levels of caspase-1 and IL-1β. MSU reduced intracellular K + concentration which was prevented by DPO-1 and siRNAs against Kv1.5. MSU increased expression of Hsp70, and Kv1.5 on the plasma membrane. siRNAs against Hsp70 were suppressed but heat shock increased the expression of Hsp70, caspase-1, IL-1β, and Kv1.5 in MSU-stimulated J774.1 cells. The CM from MSU-stimulated macrophages enhanced the expression of caspase-1, IL-1β and Kv1.5 with increased Kv1.5-mediated currents that shortened action potential duration in HL-1 cells. These responses were abolished by DPO-1 and a siRNA against Kv1.5. Conclusions Kv1.5 regulates MSU-induced activation of NLRP3 inflammasome in macrophages. MSUrelated activation of NLRP3 inflammasome and electrical remodeling in HL-1 cells are via macrophages. Kv1.5 may have therapeutic value for diseases related to gout-induced activation of the NLRP3 inflammsome, including AF.