Abstract
Ischemia-reperfusion injury (IRI) is defined as the total combined damage that occurs during a period of ischemia and following the recovery of blood flow. Oxidative stress, mitochondrial dysfunction, and an inflammatory response are factors contributing to IRI-related damage that can each result in cell death. Irisin is a polypeptide that is proteolytically cleaved from the extracellular domain of fibronectin type III domain-containing protein 5 (FNDC5). Irisin acts as a myokine that potentially mediates beneficial effects of exercise by reducing oxidative stress, improving mitochondrial fitness, and suppressing inflammation. The existing literature also suggests a possible link between irisin and IRI, involving mechanisms similar to those associated with exercise. This article will review the pathogenesis of IRI and the potential benefits and current limitations of irisin as a therapeutic strategy for IRI, while highlighting the mechanistic correlations between irisin and IRI.
Highlights
Whereas improvements in pharmacological treatments and interventional therapies can recover blood perfusion in ischemic heart tissue, the recovery of blood flow can promote metabolic dysfunction associated with cell death
While many mechanisms contribute to the pathogenesis of Ischemia-reperfusion injury (IRI), we will focus on these 3 major pathways and highlight the specific roles played by irisin, a polypeptide that is proteolytically cleaved from the extracellular domain of fibronectin type III domain-containing protein 5 (FNDC5)
The decline of PGC1-α expression, a vital regulator in mitochondrial biogenesis, and its downstream target mitochondrial transcription factor A (TFAM) both impair mitochondrial biogenesis under ischemia and hypoxia conditions, causing functional deterioration following cerebral IRI [113]. Both overactivated mitochondrial fission and failing mitochondrial biogenesis can be reversed by administering exogenous irisin which triggers the expression of mitochondrial fission-related proteins (e.g., dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1)) and mitochondrial biogenesis-related molecules (e.g., PGC1-α and TFAM), in turn protecting against hepatic IRI [68]
Summary
Whereas improvements in pharmacological treatments (e.g., thrombolytic drugs) and interventional therapies (e.g., percutaneous transluminal coronary angioplasty) can recover blood perfusion in ischemic heart tissue, the recovery of blood flow (known as reperfusion) can promote metabolic dysfunction associated with cell death. Ischemia-reperfusion injury (IRI) occurs when the blood supply is restored after a temporary loss of oxygen (O2) supply (known as ischemia) [1]. As a common pathological phenomenon, IRI occurs in the context of many pathological conditions including acute coronary syndrome, hypovolemic shock, ischemic stroke, and sickle cell disease (SCD). It is currently well established that IRI involves multiple cellular mechanisms, including oxidative stress, mitochondrial dysfunction, and an inflammatory response. Irisin acts as a myokine that is hypothesized to be protective against IRI as it reduces oxidative stress, improves mitochondrial dysfunction, and suppresses inflammation
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