Small ubiquitin-like modifiers inhibitors lower blood pressure via ERK5/KLF2-dependent upregulation of the eNOS/NO pathway  

作　　者：Nannan Tang Jiatong Li Zhuo Wang Jinlu Zuo Zifeng Zhang Di Huang Yannan Han Yuqing Chen Yilin Sun Xiang Li Ruxue Mu Qingxue Ma Jie Zhang Jiaying Wu He Wang Hongxia Zhao Xingli Dong Zhiguo Wang Yu Liu Dan Zhao Baofeng Yang 

机构地区：[1]State Key Laboratory of Frigid Zone Cardiovascular Diseases(SKLFZCD),Department of Pharmacology(State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin 150081,China [2]State Key Laboratory of Systems Medicine for Cancer,Shanghai Cancer Institute,Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200032,China [3]Biliary and Pancreatic Surgery,Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [4]Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070),Chinese Academy of Medical Sciences,Harbin 150081,China [5]Department of Clinical Pharmacy,The Second Affiliated Hospital,Harbin Medical University,Harbin 150081,China

出　　处：《Frigid Zone Medicine》2024年第4期202-211,共10页寒地医学(英文)

基　　金：supported by the National Natural Science Foundation of China(82330011,U21A20339);the CAMS Innovation Fund for Medical Sciences(CIFMS,2020-I2M-5-003);the National Natural Science Foundation of China(No.82370302,31871175);Natural Science Foundation of Heilongjiang Province of China(No.YQ2019H003);College of Pharmacy,Harbin Medical University Excellent Young Talents Funding(No.2020-YQ-01).

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.

关 键 词：hypertension SUMO inhibitor ERK5 SUMOYLATION KLF2 

分 类 号：R54[医药卫生—心血管疾病]