Small ubiquitin-like modifiers inhibitors lower blood pressure via ERK5/KLF2-dependent upregulation of the eNOS/NO pathway
Year: 2024
Type: article
Abstract: 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 coimmunoprecipitation (co-IP) and immunofluorescence (IF). NO levels were analyzed by IF. The expression levels of KLF2 and p-eNOS were semiquantified 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 pretreatment 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.
Source: Frigid Zone Medicine
Authors: 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
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid:
OpenAlex ID: W4406863672