摘要Background:Small ubiquitin-like modifiers(SUMO)ylation is a dynamic and reversible post-translational modification playing pivotal roles in the regulation of cancer,diabetes,heart failure,and neurological diseases.However,whether SUMO inhibitors also have anti-hypertension effect remains yet to be explored.Methods:Blood pressure was monitored in spontaneously hypertensive rats(SHR)after Tannic acid(TA)administration for 4 weeks.The contents of nitric oxide(NO)and endothelin-1(ET-1)in the serum of SHR were measured.Isolated endothelium-intact mesenteric artery rings were used to study relaxation effect of SUMO inhibitors.ERK5 SUMOylation was determined using co-immunoprecipitation(co-IP)and immunofluorescence(IF).NO levels were analyzed by IF.The expression levels of KLF2 and p-eNOS were semi-quantified by Western blot analysis.The transcriptional activity of eNOS promotor was assayed using ChIP-PCR.Results:Three SUMO inhibitors all reduced the phenylephrine(PE)-induced contraction of mesenteric artery rings in a concentration-dependent manner.Co-IP revealed that ponatinib promoted ERK5 SUMOylation,which was nulled following pre-treatment with the SUMO inhibitors.IF displayed that TA increased ERK5 accumulation and its co-localization with SUMO-1 in the nucleus.ChIP-PCR unveiled TA-induced enhancement of KLF2-dependent eNOS promoter activity and upregulation of eNOS/NO expression in HUVECs.In vivo,TA significantly lowered the blood pressure and improved the vascular reactivity by activating the KLF2/eNOS/NO pathway.Additionally,the level of NO was elevated along with decreased ET-1 levels in the serum of SHR.Conclusions:SUMO inhibitors inhibit ERK5 SUMOylation to promote KLF2-eNOS/NO signaling,indicating their therapeutic potential for the treatment of hypertension.