C/EBP-β-mediated upregulation of CaV1.2 calcium channel increases arterial constriction in mice with ibrutinib-associated hypertension

Ibrutinib, a Bruton's tyrosine kinase inhibitor, is indicated for treating chronic lymphocytic leukemia (CLL), but hypertension is a common cardiovascular adverse event. Previous studies have linked ibrutinib to cardiac events through dysregulated intracellular calcium handling, but the mechanisms underlying ibrutinib-associated hypertension remain largely unknown. Here, we followed up 225 CLL patients receiving ibrutinib or managed with watch-and-wait strategy, and identified ibrutinib as an independent risk factor for hypertension. In mice, ibrutinib elevated arterial blood pressure (BP) without structural remodeling of small arteries, and it potentiated K + -induced vasoconstriction. In vascular smooth muscle cells (VSMCs), ibrutinib upregulated Ca V 1.2 channel expression and function, as evidenced by enhanced Ca V 1.2 currents and K + -triggered-[Ca 2+ ] i elevation. Mechanistically, ibrutinib suppressed casein kinase 2 (CK2)-mediated HSP90β phosphorylation, and stabilized C/EBP-β, which bound to the promoter of Cacna1c gene and drove CaV1.2 transcription. Significantly, C/EBP-β knockdown attenuated ibrutinib-induced Ca V 1.2 hyperactivity and vasoconstriction. Collectively, these findings reveal a CK2-HSP90β-C/EBP-β-Ca V 1.2 signaling cascade through which ibrutinib enhances vascular Ca 2+ influx and vasoconstriction, thereby elevating arterial BP. Thus, this study nominates C/EBP-β as a therapeutic target for ibrutinib-associated hypertension.