各种来源的果胶能抑制半乳糖凝集素-3 相关的心脏纤维化。

Pectins from various sources inhibit galectin-3-related cardiac fibrosis.

机构信息

Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB, Groningen, the Netherlands.

scPharmaceuticals, Lexington, MA 02421-3105, MA, USA.

出版信息

Curr Res Transl Med. 2022 Jan;70(1):103321. doi: 10.1016/j.retram.2021.103321. Epub 2021 Nov 23.

DOI:10.1016/j.retram.2021.103321

PMID:34826684

Abstract

PURPOSE OF THE STUDY

A major challenge in cardiology remains in finding a therapy for cardiac fibrosis. Inhibition of galectin-3 with pectins attenuates fibrosis in animal models of heart failure. The purpose of this study is to identify pectins with the strongest galectin-3 inhibitory capacity. We evaluated the in vitro inhibitory capacity, identified potent pectins, and tested if this potency could be validated in a mouse model of myocardial fibrosis.

METHODS

Various pectin fractions were screened in vitro. Modified rhubarb pectin (EMRP) was identified as the most potent inhibitor of galectin-3 and compared to the well-known modified citrus pectin (MCP). Our findings were validated in a mouse model of myocardial fibrosis, which was induced by angiotensin II (Ang II) infusion.

RESULTS

Ang II infusion was associated with a 4-5-fold increase in fibrosis signal in the tissue of the left ventricle, compared to the control group (0•22±0•10 to 1•08±0•53%; P < 0•001). After treatment with rhubarb pectin, fibrosis was reduced by 57% vs. Ang II alone while this reduction was 30% with the well-known MCP (P = NS, P < 0•05). Treatment was associated with a reduced cardiac inflammatory response and preserved cardiac function.

CONCLUSION

The galectin-3 inhibitor natural rhubarb pectin has a superior inhibitory capacity over established pectins, substantially attenuates cardiac fibrosis, and preserves cardiac function in vivo. Bioactive pectins are natural sources of galectin-3 inhibitors and may be helpful in the prevention of heart failure or other diseases characterized by fibrosis.

FUNDING

Dr. Meijers is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10, University Medical Center Groningen and by the Netherlands Heart Foundation (Dekkerbeurs 2021)Dr. de Boer is supported by the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21; CVON RED-CVD, grant 2017-11; CVON PREDICT2, grant 2018-30; and CVON DOUBLE DOSE, grant 2020B005), by a grant from the leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN), and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF).

摘要

研究目的

心脏病学的一个主要挑战仍然是寻找治疗心脏纤维化的方法。用果胶抑制半乳糖凝集素-3可减轻心力衰竭动物模型的纤维化。本研究的目的是确定具有最强半乳糖凝集素-3抑制能力的果胶。我们评估了体外抑制能力，确定了有效的果胶，并在心肌纤维化的小鼠模型中测试了这种效力是否可以得到验证。

方法

在体外筛选了各种果胶级分。改性大黄果胶（EMRP）被鉴定为半乳糖凝集素-3的最强抑制剂，并与著名的改性柑橘果胶（MCP）进行了比较。我们的发现通过血管紧张素 II（Ang II）输注诱导的心肌纤维化小鼠模型得到了验证。

结果

与对照组（0·22±0·10 至 1·08±0·53%；P<0·001）相比，Ang II 输注与左心室组织纤维化信号增加 4-5 倍。用大黄果胶治疗后，纤维化减少了 57%，而 Ang II 单独治疗时减少了 30%，与著名的 MCP 治疗时减少了 30%（P=NS，P<0·05）。治疗与心脏炎症反应减少和心脏功能保存有关。

结论

半乳糖凝集素-3抑制剂天然大黄果胶对已建立的果胶具有优越的抑制能力，可显著减轻心肌纤维化，并在体内保存心脏功能。生物活性果胶是半乳糖凝集素-3抑制剂的天然来源，可能有助于预防心力衰竭或其他纤维化特征的疾病。

资金

Meijers 博士得到了 2020-10 届青年科学硕士班 Mandema 奖学金、格罗宁根大学医学中心和荷兰心脏基金会（Dekkerbeurs 2021）的支持；de Boer 博士得到了荷兰心脏基金会（CVON SHE-PREDICTS-HF，资助 2017-21；CVON RED-CVD，资助 2017-11；CVON PREDICT2，资助 2018-30；CVON DOUBLE DOSE，资助 2020B005）、莱顿杜克基金会（治愈磷脂蛋白 N 诱导的心肌病（Cure-PLaN））和欧洲研究理事会（ERC 合作组 818715、SECRETE-HF）的资助。