Short-Term Proteasome Inhibition: Assessment of the Effects of Carfilzomib and Bortezomib on Cardiac Function, Arterial Stiffness, and Vascular Reactivity.

IF 3.6 3区 生物学 Q1 BIOLOGY
Callan D Wesley, Annarita Sansonetti, Cedric H G Neutel, Dustin N Krüger, Guido R Y De Meyer, Wim Martinet, Pieter-Jan Guns
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引用次数: 0

Abstract

Proteasome inhibitors such as bortezomib and carfilzomib induce apoptosis and are a cornerstone in the treatment of relapsed or refractory multiple myeloma. However, concerns have emerged concerning their link to cancer therapy-related cardiovascular dysfunction (CTRCD). Bortezomib, a reversible first-generation inhibitor, and carfilzomib, a second-generation irreversible inhibitor, are associated with hypertension, heart failure, and cardiac arrhythmias. The current study investigated the effects of bortezomib and carfilzomib on cardiac (left ventricular ejection fraction, LVEF) and vascular (arterial stiffness, vascular reactivity) function. Cardiac function assessment aimed to build upon existing evidence of proteasome inhibitors CTRCD, while arterial stiffness served as an early indicator of potential vascular remodeling. Groups of 12-week-old C57BL/6J male mice (n = 8 per group) were randomly assigned to receive vehicle, carfilzomib (8 mg/kg I.P.), or bortezomib (0.5 mg/kg I.P.). Additionally, proteasome inhibition was assessed in mice treated with L-NAME (0.5 mg/kg) to induce hypertension. Cardiac and vascular parameters were evaluated via echocardiography on days 0 and 3. On day 6, mice were sacrificed for ex vivo analysis of arterial stiffness and vascular reactivity. Overall, no changes in arterial stiffness were detected either in vivo or ex vivo at basal pressures. However, a steeper pressure-stiffness curve was observed for carfilzomib in normotensive (p < 0.01) and hypertensive (p < 0.0001) mice ex vivo. Additionally, in hypertensive mice, carfilzomib decreased LVEF (p = 0.06), with bortezomib exhibiting similar trends. Vascular reactivity remained largely unchanged, but proteasome inhibition tended to enhance endothelial-independent relaxations in both control and hypertensive mice. In conclusion, short-term treatment with carfilzomib and bortezomib is considered relatively safe for the protocols assessed in the study.

蛋白酶体短期抑制:评估卡非佐米和硼替佐米对心脏功能、动脉僵硬度和血管反应性的影响。
硼替佐米和卡非佐米等蛋白酶体抑制剂可诱导细胞凋亡,是治疗复发性或难治性多发性骨髓瘤的基石。然而,人们开始担心它们与癌症治疗相关的心血管功能障碍(CTRCD)有关。第一代可逆抑制剂硼替佐米和第二代不可逆抑制剂卡非佐米与高血压、心力衰竭和心律失常有关。本研究调查了硼替佐米和卡非佐米对心脏(左室射血分数,LVEF)和血管(动脉僵硬度,血管反应性)功能的影响。心脏功能评估旨在以蛋白酶体抑制剂CTRCD的现有证据为基础,而动脉僵化则是潜在血管重塑的早期指标。12周大的C57BL/6J雄性小鼠(每组8只)被随机分配接受药物、卡非佐米(8毫克/千克静脉注射)或硼替佐米(0.5毫克/千克静脉注射)治疗。此外,用 L-NAME(0.5 毫克/千克)诱导高血压,对小鼠的蛋白酶体抑制作用进行评估。第0天和第3天,通过超声心动图评估心脏和血管参数。第 6 天,小鼠被处死,以便对动脉僵化和血管反应性进行体外分析。总体而言,无论是体内还是体外,在基础压力下均未检测到动脉僵化的变化。然而,在正常血压(p < 0.01)和高血压(p < 0.0001)小鼠体内外,观察到卡非佐米的压力-僵化曲线更陡峭。此外,在高血压小鼠中,卡非佐米降低了LVEF(p = 0.06),硼替佐米也表现出类似的趋势。血管反应性基本保持不变,但蛋白酶体抑制往往会增强对照组和高血压小鼠内皮依赖性松弛。总之,在本研究评估的方案中,卡非佐米和硼替佐米的短期治疗被认为是相对安全的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biology-Basel
Biology-Basel Biological Science-Biological Science
CiteScore
5.70
自引率
4.80%
发文量
1618
审稿时长
11 weeks
期刊介绍: Biology (ISSN 2079-7737) is an international, peer-reviewed, quick-refereeing open access journal of Biological Science published by MDPI online. It publishes reviews, research papers and communications in all areas of biology and at the interface of related disciplines. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.
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