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Small ubiquitin-like modifiers inhibitors lower blood pressure via ERK5/KLF2-dependent upregulation of the eNOS/NO pathway
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
2024, 4(4): 202-211. doi: 10.1515/fzm-2024-0020
Keywords: hypertension, SUMO inhibitor, ERK5, SUMOylation, KLF2
  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.
LncRNA-TUG1 as a potential diagnostic biomarker for coronary atherosclerotic heart disease
Xin Wang, Xuyao Ji, Siyao Zhang, Benzhi Cai, Yu Liu
2025, 5(4): 231-241. doi: 10.1515/fzm-2025-0025
Keywords: coronary atherosclerotic heart disease, long non-coding RNAs-taurine upregulated gene 1, biomarker
  Objectives  Accumulating evidence suggests that people living in cold regions have a higher risk of developing coronary atherosclerotic heart disease (CHD). Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis and treatment of a variety of diseases. The present study aimed to investigate the serum level of lncRNA-taurine upregulated gene 1 (TUG1) in patients with CHD and assess its potential as a diagnostic biomarker. This study aimes to investigate the serum level of lncRNA-TUG1 in patients with CHD and assess its potential as a diagnostic biomarker.  Methods  The Gene Expression Omnibus (GEO) database was employed to identify the potential lncRNAs serving as biomarkers for CHD. To validate lncRNA-TUG1, 232 subjects were enrolled in both test and diagnostic cohorts. Serum lncRNA-TUG1 levels were measured by RT-qPCR. The association between lncRNA-TUG1 levels and CHD severity was analyzed using Pearson's correlation test. Diagnostic value was assessed by receiver operating characteristic (ROC) curve analysis and compared with established cardiac biomarkers.  Results  LncRNA-TUG1 was identified in the GEO database as a potential biomarker for CHD. Serum lncRNA-TUG1 levels were significantly higher in CHD patients compared with healthy controls and non-CHD patients. CRP levels also differed between CHD and non-CHD groups, while other biomarkers showed no significant differences. ROC curve analysis demonstrated that lncRNA-TUG1 could distinguish CHD from non-CHD patients, with an area under the curve (AUC) of 0.8916, which was higher than that of conventional biomarkers such as cTnI. At a cut-off value of 2.311, the sensitivity and specificity of lncRNA-TUG1 were 61.63% and 97.67%, respectively, surpassing the diagnostic performance of cTnI. Furthermore, lncRNA-TUG1 levels in CHD patients were positively correlated with SYNTAX scores from coronary angiography and increased with the severity of vascular stenosis.  Conclusion  Elevated serum lncRNA-TUG1 levels in CHD patients suggest that lncRNA-TUG1 may serve as a novel and valuable diagnostic biomarker for CHD, with potential utility in differentiating CHD from other cardiac diseases.