Irisin: A Promising Target for Ischemia-Reperfusion Injury Therapy

Figure 1

The pathogenesis of ischemia-reperfusion injury on oxidative stress, mitochondrial dysfunction, and the inflammatory response. (1) Oxidative stress occurs and deteriorates with the progression of IRI. In the xanthine oxidase system, XD translates into XO during ischemia; meanwhile, ATP degrades to the XO substrate hypoxanthine, both of which accumulate greatly in ischemic tissues. During reperfusion, the final electron acceptor O₂ pours into ischemic tissues, causing the transformation from hypoxanthine into uric acid, and the release of superoxide O₂^•-, ^•OH, H₂O₂, and ROS. In the NADPH oxidase system, NOX is activated by both activated HIF-1α during ischemia and increased cytokines during reperfusion, promoting NADPH translation into NADP⁺ and further inducing massive production of O₂^•-, H₂O₂, and ^•OH. In the NOS system, NOS catalyzes O₂ and L-Arg into L-Cit and NO using cofactor BH₄, while the content of BH₄ decreases during IRI to further induce the uncoupling of NOS and the decline of NO. NO has an effect on inhibiting vessel constriction, which may be scavenged during the period of hemolytic anemia and microvascular vasoocclusion in SCD. (2) Mitochondrial dysfunction occurs in IRI. Complex I and complex III contained in the electron transport chain release O₂^•- and H₂O₂ and produce mtROS subsequently during IRI. IRI-related mitochondrial oxidative stress and calcium overload trigger MMP collapse and mPTP opening, causing mitochondrial dysfunction. As part of a mitochondrial quality control response, damaged mitochondria may undergo fission, mitophagy, degradation, biogenesis, and fusion to initiate recovery. (3) An inflammatory response occurs during IRI, including neutrophil infiltration, proteolytic effects, and oxidative bursts, which mediate injury in several tissues. ATP: adenosine triphosphate; BH₄: tetrahydrobiopterin; HIF-1α: hypoxia-inducible factor-1α; H₂O₂: hydrogen peroxide; IRI: ischemia-reperfusion injury; L-Arg: L-arginine; L-Cit: L-citrulline; MMP: mitochondrial membrane potential; mPTP: mitochondrial permeability transition pore; mtROS: mitochondrial ROS; NADPH: nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; NOS: nitric oxide synthase; NOX: NADPH oxidase; O₂^•-: superoxide; ^•OH, hydroxyl radical; ROS: reactive oxygen; SCD: sickle cell disease; XD: xanthine dehydrogenase; XO: xanthine oxidase.