Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-07-05 Epub Date: 2024-06-07 DOI:10.1161/CIRCRESAHA.123.324110
Vandana Mallaredy, Rajika Roy, Zhongjian Cheng, Charan Thej, Cindy Benedict, May Truongcao, Darukeshwara Joladarashi, Ajit Magadum, Jessica Ibetti, Maria Cimini, Carolina Gonzalez, Venkata Naga Srikanth Garikipati, Walter J Koch, Raj Kishore
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Abstract

Background: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardiac diseases. However, the role of systemic extracellular vesicle biogenesis inhibition in HF models is not well documented and remains unclear.

Methods: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of tipifarnib, a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a [Ras associated binding protein 27a], nSMase2 [neutral sphingomyelinase 2], and Alix [ALG-2-interacting protein X]) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery were randomly assigned to groups with and without tipifarnib treatment (10 mg/kg 3 times/wk) and monitored for 8 weeks, and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies.

Results: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced left ventricular dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of tipifarnib in TAC mice reduced circulating exosomes to baseline and remarkably improved left ventricular functions, hypertrophy, and fibrosis. Tipifarnib treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR 331-5p, which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR 331-5p is crucial for inhibiting the fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR 331-5p that acts as a potent repressor for one of the fibrotic mechanisms mediated by HOXC8.

Conclusions: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.

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替法尼能减少细胞外囊泡并防止心力衰竭
背景:心力衰竭(HF)是导致全球死亡的主要原因之一。众所周知,细胞外囊泡,包括细胞外小囊泡或外泌体,及其分子货物可在多种心脏疾病中调节细胞间的通讯。然而,全身性细胞外囊泡生物生成抑制在高频模型中的作用并没有得到很好的证实,目前仍不清楚:方法:我们在小鼠横主动脉缩窄(TAC)高频模型中研究了循环外泌体在心脏功能障碍和重塑过程中的作用。重要的是,我们研究了替法尼(tipifarnib)的疗效。替法尼是最近发现的一种外泌体生物生成抑制剂,它靶向参与该小鼠高频模型外泌体生物生成的关键蛋白(Rab27a、nSMase2 [中性鞘磷脂酶 2] 和 Alix [ALG-2-交互蛋白 X])。本研究将接受TAC手术的10周龄雄性小鼠随机分配到接受和未接受替法尼治疗(10毫克/千克,3次/周)的组别,观察8周,并通过超声心动图、组织学和生化研究进行综合评估:结果:TAC使循环血浆外泌体明显升高,并明显增加了心脏左心室功能障碍、心脏肥大和纤维化。此外,注射 TAC 小鼠血浆外泌体可诱发未受 TAC 损伤的小鼠左心室功能障碍和心肌细胞肥大。相反,TAC 小鼠接受替法尼治疗后,循环中的外泌体减少到基线水平,左心室功能、肥厚和纤维化明显改善。替法尼治疗还极大地改变了TAC后循环外泌体的miRNA谱,包括在TAC循环外泌体和TAC心脏组织中高度下调的miR 331-5p。从机理上讲,miR 331-5p 通过靶向纤维化的关键调控因子 HOXC8,对抑制成纤维细胞向肌成纤维细胞的转变至关重要。对TAC小鼠进行替法尼治疗可上调miR 331-5p的表达,而miR 331-5p是HOXC8介导的纤维化机制之一的有效抑制因子:我们的研究强调了外泌体在高房颤动和纤维化过程中的病理作用。Tipifarnib介导的对外泌体生物生成和货物分拣的抑制作用可作为一种可行的策略来预防高血脂的进行性心脏重塑。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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