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Study of the mechanism of action of 4-octyl itaconate in attenuating myocardial ischemia-reperfusion injury after heart transplantation

ABSTRACT: It is important to mitigate myocardial ischemia-reperfusion (IR) injury for improving the success of heart transplantation (HT) and the quality of life of patients.4-OI is a derivative of itaconate with similar chemical properties and biological activities as itaconate. However, 4-OI could overcome the limitations of itaconate in in vivo applications such as inefficient cellular uptake and rapid metabolism, making it more suitable for exploratory studies in the therapeutic direction.In our study, we demonstrated that 4-OI is an effective therapeutic strategy against myocardial ischemia-reperfusion injury after heart transplantation.

ORGANISM(S): Mus musculus

PROVIDER: GSE298470 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Background: Ischemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without causing permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. Purpose: The primary aim of this study was to examine the effects of IPC on the relationship between ischemia duration, stunning, and infarct size in an ischemia-reperfusion injury model. The secondary aim of the study was to examine to which extent the phosphoproteomic changes induced by IPC relate to myocardial contractile function. Methods: Rats were subjected to different durations of left anterior descending artery (LAD) occlusion, with or without preceding IPC. Echocardiograms were acquired at 4 and 48 hours to assess cardiac contraction in the affected myocardial segment. Reversible akinesia was defined as the presence of myocardial akinesia at 4 hours that resolved by 48 hours; and was considered to represent myocardial stunning. Infarction size was evaluated using triphenyl tetrazolium chloride staining. Phosphoproteomic analysis was performed in heart tissue from preconditioned and non-preconditioned animals using nano-liquid chromatography-mass spectrometry. Results: Reversible akinesia was observed in a majority of the rats that were subjected to IPC and subsequently exposed to ischemia of 13.5 or 15 minutes of ischemia (83.3% [n/N] and 66.6% [n/N] respectively). Among rats without IPC, who were exposed to either 10, 11, 12 or 13.5 minutes of ischemia, reversible akinesia was observed in 0% (n/N), 17% (2/12), 0% (n/N) and 0% (n/N) of rats (p<0.001). Phosphoproteomic analysis revealed significant differential regulation of 809 phosphopeptides between IPC and non-IPC groups, with significant associations with the sarcomere, Z-disc, and actin binding. Conclusion: Our study shows that IPC preferentially induces changes in phosphosites of proteins involved in myocardial contraction, and both increases the incidence of reversible post-ischemic myocardial stunning after ischemia-reperfusion injury and reduces infarction size.

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Study of the mechanism of action of 4-octyl itaconate in attenuating myocardial ischemia-reperfusion injury after heart transplantation

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