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Exogenous Transforming Growth Factor-β1 and Its Helminth-Derived Mimic Attenuate the Heart's Inflammatory Response to Ischemic Injury and Reduce Mature Scar Size

Lookup NU author(s): Dr Rachael RedgraveORCiD, Dr Esha Singh, Dr Simon Tual-ChalotORCiD, Dr Catherine Park, Dr Darroch Hall, Dr Karim BennaceurORCiD, Professor Ioakim SpyridopoulosORCiD, Emerita Professor Helen ArthurORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2024 American Society for Investigative Pathology. Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-β1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-β1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-β1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-β1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1β and chemokine (C-C motif) ligand 2 (>50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-β1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-β signaling in the vascular endothelium.

Publication metadata

Author(s): Redgrave RE, Singh E, Tual-Chalot S, Park C, Hall D, Bennaceur K, Smyth DJ, Maizels RM, Spyridopoulos I, Arthur HM

Publication type: Article

Publication status: Published

Journal: The American Journal of Pathology

Year: 2024

Volume: 194

Issue: 4

Pages: 562-573

Print publication date: 01/04/2024

Online publication date: 11/10/2023

Acceptance date: 27/09/2023

Date deposited: 20/02/2024

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.ajpath.2023.09.014

DOI: 10.1016/j.ajpath.2023.09.014

PubMed id: 37832870

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