Tocilizumab does not ameliorate inflammation-induced left ventricular dysfunction in a collagen-induced arthritis rat model

IF 2.3 4区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Pathology Pub Date : 2024-12-27 DOI:10.1016/j.carpath.2024.107711

Ashmeetha Manilall , Lebogang Mokotedi , Sulè Gunter , Regina Le Roux , Serena Fourie , Aletta ME Millen

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引用次数: 0

Abstract

Background

Interleukin-6 (IL-6) is an attractive therapeutic target due to its diverse roles in the pathogenesis of conditions characterized by systemic inflammation. IL-6 has also been implicated in the pathophysiology of heart failure. This study aimed to investigate the impact of IL-6 receptor blockade with tocilizumab on the molecular pathways underlying systemic inflammation-induced left ventricular (LV) dysfunction in a collagen-induced arthritis (CIA) rat model.

Methods

Seventy-three Sprague-Dawley rats were divided into three groups: control (n=28), CIA (n=29), and CIA+IL-6 blocker (n=16). Inflammation was induced in the CIA and CIA+IL-6 blocker groups using bovine type II collagen emulsified in incomplete Freund's adjuvant. After arthritis onset, the CIA+IL-6 blocker group received tocilizumab for six weeks. Circulating inflammatory markers, relative LV mRNA gene expressions, and LV systolic and diastolic function were assessed.

Results

CIA rats developed LV diastolic and early-stage LV systolic dysfunction, which was not ameliorated by IL-6 blocker administration (p > 0.05). IL-6 blocker administration did not impact circulating inflammatory markers (all p > 0.05) or LV mRNA expression of inflammatory markers compared to the CIA group, nor did it reverse inflammation-induced increases in LV mRNA expression of genes involved in fibrosis and collagen turnover, regulation of titin phosphorylation, Ca²⁺ handling, mitochondrial function, or apoptosis (all p > 0.05). However, LV mRNA expressions of CD68 and LOX, genes involved in macrophage infiltration and collagen cross-linking, were increased in the CIA group (p = 0.03, p = 0.0004), but not in the CIA+IL-6 blocker group compared to controls (p > 0.05).

Conclusion

These results suggest that although IL-6 blockade by tocilizumab may prevent inflammation-induced collagen cross-linking, the current treatment regimen may not protect against inflammation-induced LV dysfunction. Therefore, the role of IL-6 in the molecular mechanisms of inflammation-induced LV dysfunction remains inconclusive.

查看原文本刊更多论文

在胶原诱导的关节炎大鼠模型中，Tocilizumab不能改善炎症诱导的左心室功能障碍。

背景：白细胞介素-6（IL-6）在以全身炎症为特征的疾病的发病机制中发挥着多种作用，因此是一个极具吸引力的治疗靶点。IL-6 也与心力衰竭的病理生理学有关。本研究旨在探讨托西珠单抗阻断IL-6受体对胶原诱发关节炎（CIA）大鼠模型中全身炎症诱发左心室（LV）功能障碍的分子通路的影响：73只Sprague-Dawley大鼠分为三组：对照组（n=28）、CIA组（n=29）和CIA+IL-6受体阻滞剂组（n=16）。CIA组和CIA+IL-6阻断剂组使用在不完全弗氏佐剂中乳化的牛Ⅱ型胶原蛋白诱发炎症。关节炎发病后，CIA+IL-6 阻断剂组接受了为期六周的托珠单抗治疗。对循环炎症标志物、左心室 mRNA 基因的相对表达以及左心室收缩和舒张功能进行了评估：结果：CIA大鼠出现了左心室舒张功能障碍和早期左心室收缩功能障碍，但服用IL-6受体阻滞剂并没有改善这些症状（p > 0.05）。与 CIA 组相比，IL-6 阻滞剂不会影响循环炎症标志物（所有 p > 0.05）或左心室炎症标志物 mRNA 的表达，也不会逆转炎症诱导的左心室 mRNA 表达增加，这些基因涉及纤维化和胶原周转、滴定蛋白磷酸化调节、Ca2+ 处理、线粒体功能或细胞凋亡（所有 p > 0.05）。然而，与对照组相比，CIA 组参与巨噬细胞浸润和胶原交联的基因 CD68 和 LOX 的 LV mRNA 表达增加（p = 0.03，p = 0.0004），但 CIA+IL-6 阻断剂组没有增加（p > 0.05）：这些结果表明，虽然托西珠单抗阻断IL-6可防止炎症诱导的胶原交联，但目前的治疗方案可能无法防止炎症诱导的左心室功能障碍。因此，IL-6在炎症诱导的左心室功能障碍的分子机制中的作用仍无定论。

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

Cardiovascular Pathology 医学-病理学

CiteScore

7.50

自引率

2.70%

发文量

审稿时长

18 days

期刊介绍： Cardiovascular Pathology is a bimonthly journal that presents articles on topics covering the entire spectrum of cardiovascular disease. The Journal''s primary objective is to publish papers on disease-oriented morphology and pathogenesis from clinicians and scientists in the cardiovascular field. Subjects covered include cardiovascular biology, prosthetic devices, molecular biology and experimental models of cardiovascular disease.