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Integrated transcriptomic and metabolomic analysis reveals the regulatory role of Itaconic acid in inflammatory infiltration during myocardial Ischemia-Reperfusion injury

cardiology
immunology
pathology
pharmacology
metabolic-sciences

Abstract

Background.

Inflammatory infiltration constitutes a fundamental pathophysiological mechanism in myocardial ischemia-reperfusion (IR) injury, characterized by its role in initiating tissue damage, amplifying pathological inflammatory cascades, and exacerbating structural and functional impairment of the myocardium. The identification of novel mechanisms underlying inflammatory infiltration in IR injury, utilizing integrated transcriptomics and metabolomics, is of paramount importance.

Methods.

Following the establishment of a myocardial ischemia-reperfusion model, tissue samples from the infarct border zone were harvested for transcriptomics and wide-target metabolomic sequencing. Bioinformatics methods were used to analyze the transcriptomics and metabolomics results separately and to perform a joint analysis. Molecular docking and molecular dynamics modeling were employed to explore proteins bound to itaconic acid. Following intragastric administration of 4-octyl itaconate (4-OI) to myocardial IR mice, echocardiography was performed. Plasma levels of IL-4, IL-10, cTnT, and CK-MB were assessed using an ELISA kit, myocardial inflammatory infiltration was assessed via HE staining, M1 and M2 macrophage infiltration was evaluated via iNOS and Arg1 immunohistochemical staining, and mRNA expression levels of IL-1β, TNF-α, IL-4, and IL-10 in myocardial tissue were measured via qRT-PCR, and measured mRNA expression levels of IL-1β, TNF-α, IL-4, and IL-10 in myocardial tissue via qRT-PCR.

Results.

Integrated transcriptomic and metabolomic analysis identified Itaconic acid as a key metabolite modulating myocardial IR injury, with good interaction with Pla2g2d, Lcn2, and Gpr55 proteins. Itaconic acid significantly improved myocardial IR injury in mice, increased M2 macrophage infiltration in the infarct margin zone, and reduced inflammatory infiltration levels.

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