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.

中文翻译：

---

Tipifarnib 减少细胞外囊泡并预防心力衰竭。


背景技术心力衰竭(HF)是全世界死亡的主要原因之一。细胞外囊泡，包括小细胞外囊泡或外泌体，及其分子货物已知可调节多种心脏病期间的细胞间通讯。然而，系统性细胞外囊泡生物发生抑制在心力衰竭模型中的作用尚未得到充分记录，且仍不清楚。方法我们研究了循环外泌体在心力衰竭小鼠横主动脉缩窄（TAC）模型中心脏功能障碍和重塑过程中的作用。重要的是，我们研究了替比法尼（tipifarnib）的功效，替比法尼是一种最近发现的外泌体生物合成抑制剂，其靶向涉及的关键蛋白（Rab27a [Ras 相关结合蛋白 27a]、nSMase2 [中性鞘磷脂酶 2] 和 Alix [ALG-2 相互作用蛋白 X]）在该 HF 小鼠模型的外泌体生物发生中。在这项研究中，接受 TAC 手术的 10 周龄雄性小鼠被随机分为接受和不接受替比法尼治疗组（10 mg/kg 3 次/周），并进行为期 8 周的监测，并通过超声心动图进行综合评估。组织学和生化研究。结果 TAC 显着升高循环血浆外泌体，并显着增加心脏左心室功能障碍、心脏肥大和纤维化。此外，注射TAC小鼠的血浆外泌体可诱导未受伤且未注射TAC的小鼠左心室功能障碍和心肌细胞肥大。相反，TAC 小鼠接受替比法尼治疗可将循环外泌体减少至基线，并显着改善左心室功能、肥厚和纤维化。 Tipifarnib 治疗还极大地改变了 TAC 后循环外泌体的 miRNA 谱，包括 miR 331-5p，其在 TAC 循环外泌体和 TAC 心脏组织中均高度下调。从机制上讲，miR 331-5p 通过靶向纤维化的关键调节因子 HOXC8，对于抑制成纤维细胞向肌成纤维细胞的转变至关重要。 TAC 小鼠中的替比法尼治疗上调了 miR 331-5p 的表达，miR 331-5p 是 HOXC8 介导的纤维化机制之一的有效抑制因子。结论我们的研究强调了外泌体在压力超负荷引起的心力衰竭和纤维化中的病理作用。替比法尼介导的外泌体生物发生和货物分选的抑制可能作为预防心力衰竭进行性心脏重塑的可行策略。