4-Octyl Itaconate Alleviates Myocardial Ischemia-Reperfusion Injury Through Promoting Angiogenesis via ERK Signaling...

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Inflammation Research

Background:

• Myocardial ischemia-reperfusion (IR) injury is a significant clinical challenge after revascularization for ischemic heart disease.
• Itaconate, a metabolite from macrophages, plays roles in inflammation and metabolism.
• Understanding itaconate's protective mechanisms could reveal new therapeutic targets.

Purpose of the Study:

• To investigate the protective effects of itaconate derivatives against myocardial IR injury.
• To identify the molecular targets and signaling pathways involved in itaconate's cardioprotection.
• To evaluate the therapeutic potential of 4-Octyl itaconate (4-OI) in a preclinical model.

Main Methods:

• Utilized a mouse model of myocardial IR injury.
• Administered 4-Octyl itaconate (4-OI) for 7 days and assessed cardiac function.
• Employed RNA sequencing, molecular docking, and cell culture studies.
• Investigated the role of Immune-Responsive Gene1 (IRG1) and Mitogen-Activated Protein Kinases (MAPK) signaling, specifically Extracellular Signal-Regulated Kinase (ERK).

Main Results:

• 4-OI administration reduced myocardial damage, enhanced angiogenesis, and alleviated hypoxia during reperfusion.
• 4-OI promoted endothelial cell proliferation and migration via MAPK/ERK signaling activation.
• Inhibition of itaconate synthesis exacerbated IR injury, while 4-OI supplementation mitigated this effect.
• 4-OI was found to activate MAPK signaling through FMS-like tyrosine kinase 1 (Flt1).

Conclusions:

• Exogenous 4-Octyl itaconate (4-OI) demonstrates significant cardioprotective effects against ischemia-reperfusion injury.
• 4-OI promotes angiogenesis by activating the MAPK/ERK signaling pathway, potentially via Flt1.
• Itaconate derivatives represent a promising therapeutic avenue for managing myocardial IR injury.