MLN4924, A Neddylation Inhibitor, Improves the Vascular Reactivity but Causes Early Mortality in Polymicrobial Sepsis: Effect on Vascular RhoA/ROCK Signaling.

IF 3.7 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Cardiovascular Toxicology Pub Date : 2025-09-01 Epub Date: 2025-07-08 DOI:10.1007/s12012-025-10039-x
Divyanshi Gupta, Raut Akash, S Simran Kour, Ballabh Dangra, Sonam Kumari, Himani Pandey, Soumen Choudhury, Amit Shukla, Neeraj K Gangwar, Shyama N Prabhu
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引用次数: 0

Abstract

Vascular hyporeactivity is one of the the leading causes of death in sepsis. Ubiquitylation regulates the turnover of different cellular proteins; however, its role in controlling vascular dysfunction in sepsis is largely unknown. Herein, we aimed to evaluate the role of Cullin-3-RING ubiquitin ligase in regulating vascular contractile protein (RhoA) homeostasis and thereby regulating sepsis-induced vascular dysfunction. Sepsis was induced by caecal ligation and puncture (CLP) in mice. Cullin neddylation inhibitor (MLN4924) was evaluated for its possible therapeutic use in experimental sepsis in mice. Sepsis significantly impaired vascular RhoA/ROCK signaling as corroborated by marked increase in vasorelaxant response to Y-27632 (a Rho kinase inhibitor) which was found to be mediated by iNOS/NO/sGC pathway. Further, a significant down-expression of vascular RhoA/ROCK in septic mice was accompanied with increase in the protein expression of neddylated cullin3. Additionally, the silencing of cullin3 in vascular smooth muscle cells resulted in increase in the protein expression of RhoA. Treatment of septic mice with MLN4924, a neddylation inhibitor, significantly improved the vascular reactivity as evidenced by reduction in relaxant response to Y-27632, increase in protein level of RhoA in aorta with concomitant restoration of the contractile response to nor-adrenaline. However, MLN4924 treated mice showed higher bacterial load in blood, peritoneal lavage, lungs and spleen of septic mice. Taken together, sepsis-induced increase in cullin3 mediated degradation of RhoA possibly contributes to the vascular hyporeactivity. Thus, inhibition of vasculo-specific cullin neddylation by MLN4924 seems a potential therapeutic target for treating sepsis-induced vascular dysfunctions.

泛素化抑制剂MLN4924改善多微生物脓毒症的血管反应性但导致早期死亡:对血管RhoA/ROCK信号的影响
血管反应性低下是导致败血症死亡的主要原因之一。泛素化调节不同细胞蛋白的周转;然而,它在脓毒症中控制血管功能障碍的作用在很大程度上是未知的。在此,我们旨在评估Cullin-3-RING泛素连接酶在调节血管收缩蛋白(RhoA)稳态中的作用,从而调节败血症诱导的血管功能障碍。采用盲肠结扎穿刺法(CLP)诱导小鼠脓毒症。Cullin类化化抑制剂(MLN4924)对实验性小鼠脓毒症的治疗价值进行了评价。脓毒症显著损害血管RhoA/ROCK信号,Y-27632(一种Rho激酶抑制剂)的血管松弛剂反应显著增加,这被发现是由iNOS/NO/sGC途径介导的。此外,脓毒症小鼠血管RhoA/ROCK的显著下调伴随着类木化cullin3蛋白表达的增加。此外,cullin3在血管平滑肌细胞中的沉默导致RhoA蛋白表达增加。用类化化抑制剂MLN4924治疗脓毒症小鼠,可以显著改善血管反应性,Y-27632的松弛反应减少,主动脉RhoA蛋白水平增加,同时对无肾上腺素的收缩反应恢复。然而,MLN4924处理的小鼠在脓毒症小鼠的血液、腹腔灌洗液、肺和脾脏中显示出更高的细菌负荷。综上所述,败血症诱导的cullin3介导的RhoA降解增加可能导致血管反应性降低。因此,MLN4924抑制血管特异性cullin类化修饰似乎是治疗败血症诱导的血管功能障碍的潜在治疗靶点。
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来源期刊
Cardiovascular Toxicology
Cardiovascular Toxicology 医学-毒理学
CiteScore
6.60
自引率
3.10%
发文量
61
审稿时长
>12 weeks
期刊介绍: Cardiovascular Toxicology is the only journal dedicated to publishing contemporary issues, timely reviews, and experimental and clinical data on toxicological aspects of cardiovascular disease. CT publishes papers that will elucidate the effects, molecular mechanisms, and signaling pathways of environmental toxicants on the cardiovascular system. Also covered are the detrimental effects of new cardiovascular drugs, and cardiovascular effects of non-cardiovascular drugs, anti-cancer chemotherapy, and gene therapy. In addition, Cardiovascular Toxicology reports safety and toxicological data on new cardiovascular and non-cardiovascular drugs.
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