Small ubiquitin-like modifiers inhibitors lower blood pressure via ERK5/KLF2-dependent upregulation of the eNOS/NO pathway
Nannan Tang1
Jiatong Li2
Zhuo Wang1
Jinlu Zuo1
Zifeng Zhang1
Di Huang3
Yannan Han1
Yuqing Chen1
Yilin Sun1
Xiang Li1
Ruxue Mu1
Qingxue Ma1
Jie Zhang1
Jiaying Wu1
He Wang1
Hongxia Zhao4
Xingli Dong1
Zhiguo Wang1
Yu Liu1
Dan Zhao3
Baofeng Yang4
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,China2.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;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;Biliary and Pancreatic Surgery,Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China3.Department of Clinical Pharmacy,The Second Affiliated Hospital,Harbin Medical University,Harbin 150081,China4.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;Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070),Chinese Academy of Medical Sciences,Harbin 150081,China
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.
机标关键词：pressureinhibitorspathwaysmallenosbloodklf2-dependentlower
论文发表日期：2024-10-30
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：10( 202-211 )
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