Phosphoregulation of signal transduction pathways in ischemia and reperfusion.
Ischemia/reperfusion (I/R) injury triggered by pathogenic processes, such as organ transplant dysfunction, stroke, myocardial infarction, and shock, stimulate both immune and inflammatory pathways. Inflammatory cell activation and cytotoxic cytokine expression are associated with reperfusion injury. The activation of these inflammatory mediators initiates several interconnected downstream cascades regulated by phosphorylation and dephosphorylation reactions. These complex phosphorylation-dependent signal transduction pathways ultimately initiate nuclear transcription of inflammatory as well as anti-inflammatory genes to repair and assist in the recovery of damaged cells. Radical oxygen species (ROS) production, under ischemic conditions, initiates a cascade of events regulated by phosphorylation/dephosphorylation reactions and inflammatory gene expression. This is a review of the current understanding of the phosphoregulatory mechanisms that mediate the complex processes of signal transduction secondary to I/R injury. The rationale for inhibiting or activating signaling pathways as a promising molecular target for ameliorating reperfusion injury in I/R-related diseases, such as stroke, myocardial infarction, and storage for transplantation, is discussed on the basis of a new understanding of the mechanisms modulating phosphoregulatory pathways. In addition, we present part of our ongoing research in this field with phosphoregulatory signal transduction and its potential application.
López-Neblina
Fernando
F
Trauma, Surgery Research and Molecular Biology, Borgess Research Institute, Kalamazoo, MI 49048, USA.
Toledo-Pereyra
Luis H
LH
D000818:Animals; D006706:Homeostasis; D006801:Humans; D007109:Immunity; D007249:Inflammation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases