Current State and Novel Approaches of Antiplatelet Therapy

Metharom, Pat; Berndt, Michael C.; Baker, Ross; Andrews, Robert K.

doi:10.1161/atvbaha.114.303413

Cited by 64 publications

(42 citation statements)

References 140 publications

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“…To understand possible mechanisms controlling this process, we treated platelets with various receptor antagonists currently under evaluation for inhibition of shear-mediated platelet activation. 19 Among the inhibitors tested, the thromboxane receptor antagonist ICI185,282 reduced shear-mediated release of CCL5, whereas blockade of αIIbβ3 integrin, α2β1 integrin, and P2Y 12 was without effect (online-only Data Supplement Figure XII). …”

Section: Resultsmentioning

confidence: 99%

Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment

et al. 2016

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BACKGROUND Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the context of arterial myeloid cell recruitment. METHODS Intravital microscopy of the carotid artery, the jugular vein, and cremasteric arterioles and venules in Apoe−/− and CatG-deficient mice (Apoe−/−Ctsg−/−) was used to study site-specific myeloid cell behavior after high-fat diet feeding or tumor necrosis factor stimulation. Atherosclerosis development was assessed in aortic root sections after 4 weeks of high-fat diet, whereas lung inflammation was assessed after inhalation of lipopolysaccharide. Endothelial deposition of CatG and CCL5 was quantified in whole-mount preparations using 2-photon and confocal microscopy. RESULTS Our observations elucidated a crucial role for CatG during arterial leukocyte adhesion, an effect not found during venular adhesion. Consequently, CatG deficiency attenuates atherosclerosis but not acute lung inflammation. Mechanistically, CatG is immobilized on arterial endothelium where it activates leukocytes to firmly adhere engaging integrin clustering, a process of crucial importance to achieve effective adherence under high-shear flow. Therapeutic neutralization of CatG specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of CatG-neutralizing antibodies permitted inhibition of atherogenesis in mice. CONCLUSIONS Taken together, these findings present evidence of an arterial-specific recruitment pattern centered on CatG-instructed adhesion strengthening. The inhibition of this process could provide a novel strategy for treatment of arterial inflammation with limited side effects.

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Section: Resultsmentioning

confidence: 99%

Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment

et al. 2016

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“…ADAM17 is a sheddase for GPIbα [41] and GPV [42] of the GPIb–IX–V complex, which has a variety of ligands including von Willebrand factor (vWF), thrombin, coagulation factors XI and XII, P-selectin, and the leukocyte integrin αMβ2 [43]. GPIb-IX-V is essential for hemostasis and GPVI has a minor role, but both are potential anti-platelet drug targets because they promote thrombosis [44]. The physiological role of their shedding is not clear, since mice with platelets deficient in ADAM10, ADAM17, or both have normal platelet size and count [37].…”

Section: Adam10 and Adam17: Ubiquitous And Essential “Molecular Scissmentioning

confidence: 99%

“…This would help to explain why GPVI is not cleaved in resting platelets, but is rapidly cleaved in response to various stimuli including its physiological ligand collagen, shear stress, activated coagulation factor Xa, GPVI antibodies, and other platelet-activating agonists [47]. Since GPVI is regarded as a promising anti-platelet drug target to treat thrombosis [44], the induction of GPVI shedding by targeting the Tspan14–ADAM10 complex has some potential.…”

Section: Regulation Of Adam10 By Tetraspaninsmentioning

confidence: 99%

Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids

et al. 2016

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A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are ubiquitous transmembrane “molecular scissors” which proteolytically cleave, or shed, the extracellular regions of other transmembrane proteins. ADAM10 is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions. ADAM17 is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor α (TNFα) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function. However, the regulation of ADAM10 and ADAM17 trafficking and activation are not fully understood. This review will describe how the TspanC8 subgroup of tetraspanins (Tspan5, 10, 14, 15, 17, and 33) and the iRhom subgroup of protease-inactive rhomboids (iRhom1 and 2) have emerged as important regulators of ADAM10 and ADAM17, respectively. In particular, they are required for the enzymatic maturation and trafficking to the cell surface of the ADAMs, and there is evidence that different TspanC8s and iRhoms target the ADAMs to distinct substrates. The TspanC8s and iRhoms have not been studied functionally on platelets. On these cells, ADAM10 is the principal sheddase for the platelet collagen receptor GPVI, and the regulatory TspanC8s are Tspan14, 15, and 33, as determined from proteomic data. Platelet ADAM17 is the sheddase for the von Willebrand factor (vWF) receptor GPIb, and iRhom2 is the only iRhom that is expressed. Induced shedding of either GPVI or GPIb has therapeutic potential, since inhibition of either receptor is regarded as a promising anti-thrombotic therapy. Targeting of Tspan14, 15, or 33 to activate platelet ADAM10, or iRhom2 to activate ADAM17, may enable such an approach to be realized, without the toxic side effects of activating the ADAMs on every cell in the body.

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“…Ann Transl Med 2017;5 (22):449 atm.amegroups.com blocks activation caused by thrombin (e.g., voraxapar) (35). All these drugs have helped to prevent cardiovascular deaths, but it is important to mention that weak inhibition of platelet function, excessive bleeding, thrombocytopenia and unexpected platelet activation may occur but are side effects that continuously drive therapeutic research and enhancements in healthcare.…”

Section: Antiplatelet Therapies Applied In Arterial Thrombosismentioning

confidence: 99%

Platelets: an outlook from biology through evidence-based achievements in critical care

Costa-Filho

Bozza

2017

Ann. Transl. Med.

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Since the original observations by Bizzozero and Osler, we have seen tremendous advances in the understanding of platelets far beyond haemostasis and the restoration of injured endothelium. In this minireview on platelets, we will briefly outline their historical description and the importance of their evolution, focusing on a 450 million years old living fossil of Limulus polyphemus, a marine chelicerate arthropod, which helped researchers explain the basis for the immunity role of platelets and make correlations with platelet ultrastructure and function. In addition, the impact of the Limulus Amoebocyte Lysate (LAL) test for modern medicine is highlighted. The role of platelets in cardiovascular diseases, their relevance in arterial and venous thrombosis, and the utilization of antithrombotic drugs as therapeutic agents are also reported.Furthermore, platelet receptors are crucial in aggravating or mitigating other diseases, such as cancer and infections, which can recruit cells and have numerous interactions in a process recently coined "NETosis formation", which is also briefly depicted.

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Current State and Novel Approaches of Antiplatelet Therapy

Cited by 64 publications

References 140 publications

Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment

Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment

Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids

Platelets: an outlook from biology through evidence-based achievements in critical care

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