KAT7 contributes to ponatinib-induced hypertension by promoting endothelial senescence and inflammatory responses through activating NF-κB signaling pathway.

Abstract

Background and purpose: Ponatinib, a tyrosine kinase inhibitor (TKI) leads to hypertension; however, the mechanisms remain elusive. We aimed to investigate whether lysine acetyltransferase 7 (KAT7), a key regulator of cellular senescence that is closely associated with cardiovascular diseases, involves in ponatinib-induced hypertension.

Methods and results: After administering ponatinib to Sprague-Dawley (SD) rats for 8 days, we measured blood pressure, vasodilation, and endothelial function using tail-cuff plethysmography, isometric myography, and the Total NO Assay kit, respectively. The results indicated that ponatinib increased blood pressure, impaired endothelium-dependent relaxation (EDR), and caused injury to endothelial cells in SD rats. Furthermore, PCR and Western blot experiments demonstrated an upregulation of KAT7 expression in rat mesenteric artery endothelial cells (MAECs) following ponatinib treatment. To further study the role of KAT7 in ponatinib-induced hypertension, we divided the SD rats into four groups: control, ponatinib, WM-3835 (a KAT7 inhibitor), and ponatinib plus WM-3835. Notably, WM-3835 administration significantly improved ponatinib-induced hypertension and EDR dysfunction in SD rats. Mechanistically, over-expression of KAT7 (OE-KAT7) in MAECs led to cellular senescence and inflammation, phenomena that were also observed in the mesenteric arteries of ponatinib-treated rats and in MAECs exposed to ponatinib. However, WM-3835 mitigated these detrimental effects in both in vivo and in vitro experiments. Additionally, both OE-KAT7 and ponatinib treatment induced H3K14 acetylation (H3K14ac), with OE-KAT7 also elevating the recruitment of the H3K14ac to the p21 promoter. Moreover, BAY 11-7085, a nuclear factor (NF)-κB inhibitor, potently alleviated the accumulation of IL-6 and IL-8, as well as endothelial cell senescence induced by ponatinib and KAT7 overexpression.

Conclusion: Our data indicate that ponatinib-induced elevation of KAT7 led to endothelial cells senescence and inflammatory responses through H3K14 acetylation and NF-κB signaling pathway, subsequently caused vasotoxicity and hypertension.