Oxidative Stress and Its Impact on Reperfused Myocardium: Pathophysiological Insights and Therapeutic Perspectives

Figures

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  Figure 1. MIRI and Oxidative Stress: Mitochondrial Dysfunction and Calcium Overload. Reperfusion triggers excessive generation of reactive oxygen and nitrogen species (ROS/RNS) from mitochondria, NADPH oxidase, and other cellular sources, overwhelming endogenous antioxidant defenses. Oxidative stress promotes mitochondrial permeability transition pore (mPTP) opening, calcium overload, inflammasome activation, and apoptotic signaling, creating a self-amplifying cycle of mitochondrial dysfunction, inflammation, and cardiomyocyte death.

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  Figure 2. Molecular Mechanisms of Oxidative Stress and Epigenetic Regulation in Myocardial Ischemia–Reperfusion Injury. Ischemia–reperfusion induces alterations in m6A RNA methylation and downregulation of the RNA demethylase FTO, contributing to oxidative stress, inflammatory activation, pyroptosis, and cardiomyocyte injury. FTO-mediated stabilization of protective transcripts, including YAP1, may enhance cellular survival and preserve myocardial function. In parallel, PGC-1α acts as a central regulator of mitochondrial biogenesis, antioxidant defenses, and energy metabolism through interactions with Nrf2 and TFAM. The proposed crosstalk between FTO-dependent epigenetic regulation and PGC-1α-mediated mitochondrial protection may represent a novel cardioprotective mechanism and a potential therapeutic target in MIRI.

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  Figure 3. MMP9High Neutrophils and NET-Mediated Inflammation in Myocardial Ischemia–Reperfusion Injury (MIRI): Mechanisms, Clinical Correlations, and Therapeutic Implications. Ischemia–reperfusion promotes the phenotypic transition of neutrophils toward a pro-inflammatory MMP9High subset characterized by enhanced matrix metalloproteinase-9 expression, increased reactive oxygen species production, and augmented inflammatory activity. Expansion of MMP9High neutrophils is associated with elevated cardiac injury biomarkers, systemic inflammation, endothelial dysfunction, and microvascular damage. These findings highlight neutrophil heterogeneity as a key determinant of post-ischemic inflammation and identify MMP9High neutrophils as a potential therapeutic target in MIRI. *** p ≤ 0.001.

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  Figure 4. Macrophage Polarization, Metabolic Reprogramming, and HSP90–GSK3β–PKM2 Signaling Pathways in Myocardial Ischemia–Reperfusion Injury.

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  Figure 5. PANoptosis and Interconnected Cell Death Pathways.