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  • br Perspective AA LA and other PUFAs

    2023-01-28


    Perspective AA, LA and other PUFAs and their lipid metabolites play an important role in human diseases. 12/15-LOX which is the metabolic enzyme of them plays an important role in the pathogenesis-related diseases such as atherosclerosis, diabetic nephropathy, neurological diseases and other pathological processes related to growth, migration, oxidative stress, extracellular matrix production and inflammatory factor expression. Conventionally, the signal pathway of 12/15-LOX is thought to be mainly apoptosis. In recent years, researchers find that 12/15-LOX is not only involved in autophagy but also ferroptosis which is a newly defined cell death. Figuring out the way how 12/15-LOX play a part in human disease helps to discover new drug targets and develop new drugs. We discuss the possibility of 12/15-LOX that it may serve as a potential target for disease treatment. And the relationship between 12/15-LOX, diseases and the relevant types of cell death need to be further explored. It turned out that 12/15-LOX inhibitors including baicalein, PD146176, N-benzyl-N-hydroxy-5-phenylpentamidine (BHPP), nordihydroguaiaretic Phentolamine Mesylate (NDGA) have protective effects on the cell and animal models of various diseases (Table 1). However, more clinical studies are needed to confirm its role in the drug efficacy.
    Conflicts of interest
    Acknowledgments This work is partially financially supported by the National Natural Science Foundation of China (Nos. 81671293 and 81302750) and Hunan Natural Science Foundation (No. 2017JJ3479).
    Role of Platelet Activation in Hemostasis and Thrombosis Platelets are small, anucleated, megakaryocyte-derived cells that primarily function to form a hemostatic plug in response to vascular injury, thereby preventing blood loss [1]. Conversely, in occlusive thrombotic disorders, platelets play a deleterious role through the formation of potentially occlusive intravascular clots. Atherothrombosis, the most prevalent occlusive thrombotic disorder, is characterized by the formation of a platelet-rich thrombus in the lumen of a vessel in response to atherosclerotic plaque rupture [2]. Occlusive intravascular thrombi in the coronary or cerebral arteries result in ischemic heart disease or stroke, respectively, the two leading causes of mortality worldwide that account for ∼15 million deaths annually [3]. The prophylactic treatment of individuals at risk for a thrombotic event with therapeutics that reduce platelet activation has decreased the mortality associated with ischemic heart disease and stroke by ∼25% 2, 4. Despite improved clinical outcomes, patients treated with antiplatelet therapeutics continue to face a high level of mortality due to thrombosis and its associated complications; therefore, novel antiplatelet therapies with improved antithrombotic efficacy are warranted. Due to the requisite role of platelets in hemostasis, increased bleeding is an adverse effect of all clinically approved antiplatelet drugs [2]. Treatment of individuals with antiplatelet therapy must therefore balance the benefits of a decrease in thrombotic events with the subsequent risk of serious bleeding. The goal of novel antiplatelet therapy is to identify a target that potently inhibits thrombus formation while minimally altering hemostasis. The recent development of a potent and selective platelet-type 12-LOX inhibitor suggests that 12-LOX is one such novel antiplatelet therapy [5]. This review focuses on our current understanding of the role of 12-LOX in platelet function, the refinement/development of 12-LOX inhibitors, and the antiplatelet effects of novel 12-LOX inhibitors.
    Stages of Thrombus Formation Thrombus formation can be separated into distinct but overlapping stages including platelet–matrix adhesion (tethering, activation, and spreading), and platelet–platelet interaction (aggregation and stabilization) (Figure 1), which was reviewed in-depth by Jackson et al.[4]. Upon vascular injury, platelets tether indirectly to the subendothelial extracellular matrix (ECM) via interaction of the platelet glycoprotein (GP) Ib/V/IX receptor complex with the soluble plasma protein Von Willebrand factor (VWF) that is immobilized on collagen fibrils. Tethering of platelets to the ECM allows additional platelet receptors such as α2β1, α5β1, αLβ2, αIIbβ3, and αvβ3 to engage their ECM ligands, respectively. This engagment initiates platelet activation, firm adhesion, and spreading that leads to the formation of a platelet monolayer covering the injured area. One of the most well-studied platelet–ECM interactions is between collagen and its platelet receptors, GPVI and α2β1. Thrombus extension is facilitated by the platelet surface receptor αIIbβ3, creating a crossbridge between adherent platelets in the thrombi and quiescent platelets circulating through the vessel via adhesive plasma proteins, primarily fibrinogen.