Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps

Joshi, Manjunath B.; Baipadithaya, Guruprasad; Balakrishnan, Aswath; Hegde, Mangala; Vohra, Manik; Ahamed, Rayees; Nagri, Shivashankara Kaniyoor; Ramachandra, Lingadakai; Satyamoorthy, Kapaettu

doi:10.1038/srep36362

Cited by 71 publications

(49 citation statements)

References 59 publications

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“…Such traps are considered to represent an inflammatory activation of neutrophils. Mechanistically, homocysteine induces superoxide anion generated by NOX, which subsequently leads to the activation of ERK1/2 and Akt signalling related to the formation of neutrophil extracellular traps (Joshi et al ., ). Furthermore, homocysteine promotes the chemotaxis and migration of human peripheral neutrophils via NOX‐derived ROS production and subsequent activation of ERK1/2 (Alvarez‐Maqueda et al ., ).…”

Section: The Mechanisms Of Vascular Injury Induced By Hhcymentioning

confidence: 97%

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Wang

Kong

2017

British J Pharmacology

114

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Section: The Mechanisms Of Vascular Injury Induced By Hhcymentioning

confidence: 97%

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Wang

Kong

2017

British J Pharmacology

114

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“…Indeed, neutrophils that are isolated from patients with diabetes are prone to produce NETs spontaneously ( Fig. 4A) (93,95,96). Plasma nucleosome levels are increased in patients with type 2 diabetes mellitus (T2DM) (93,97).…”

Section: Diabetes and Its Complicationsmentioning

confidence: 99%

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

2018

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Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme that is critically involved in the release of decondensed chromatin from neutrophils as neutrophil extracellular traps (NETs). NETs, together with fibrin, are implicated in host defense against pathogens; however, the formation of NETs (NETosis) has injurious effects that may outweigh their protective role. For example, PAD4 activity produces citrullinated neoantigens that promote autoimmune diseases, such as rheumatoid arthritis, to which PAD4 is genetically linked and where NETosis is prominent. NETs are also generated in basic sterile inflammatory responses that are induced by many inflammatory stimuli, including cytokines, hypoxia, and activated platelets. Mice that lack PAD4-deficient in NETosis-serve as an excellent tool with which to study the importance of NETs in disease models. In recent years, animal and human studies have demonstrated that NETs contribute to the etiology and propagation of many common noninfectious diseases, the focus of our review. We will discuss the role of NETs in thrombotic and cardiovascular disease, the induction of NETs by cancers and its implications for cancer progression and cancer-associated thrombosis, and elevated NETosis in diabetes and its negative impact on wound healing, and will propose a link between PAD4/NETs and age-related organ fibrosis. We identify unresolved issues and new research directions.-Wong, S. L., Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

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“…In addition, hyperactive diabetic platelets are more reactive to leukocytes 121 and enhance NETosis. 122,123 Diabetes is also associated with an increase in PMPs 124,125 and their platelets are more effective at promoting blood coagulation.…”

Section: Diabetic Platelets and Thromboinflammationmentioning

confidence: 99%

Thromboinflammatory Functions of Platelets in Ischemia–Reperfusion Injury and Its Dysregulation in Diabetes

Maiocchi

Alwis

et al. 2018

Semin Thromb Hemost

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Ischemia-reperfusion (IR) injury is a common complication of a variety of cardiovascular diseases, including ischemic stroke and myocardial infarction (MI). While timely re-establishment of blood flow in a thrombosed artery is the primary goal of acute therapy in these diseases, paradoxically, reperfusion of ischemic tissue can cause widespread microvascular dysfunction that significantly exacerbates organ damage. Reperfusion injury is associated with activation of the humoral and cellular components of the hemostatic and innate immune systems and also with excessive reactive oxygen species production, endothelial dysfunction, thrombosis, and inflammation. Platelets are critical mediators of thromboinflammation during reperfusion injury and a hyperactive platelet phenotype may contribute to an exaggerated IR injury response. This is particularly relevant to diabetes which is characteristically associated with hyperactive platelets, significantly worse IR injury, increased organ damage, and increased risk of death. However, the mechanisms underlying vulnerability to IR injury in diabetic individuals is not well defined, nor the role of "diabetic platelets" in this process. This review summarizes recent progress in understanding the role of platelets in promoting microvascular dysfunction and inflammation in the context of IR injury. Furthermore, the authors discuss aspects of the thromboinflammatory function of platelets that are dysregulated in diabetes. They conclude that diabetes likely enhances the capacity of platelets to mediate microvascular thrombosis and inflammation during IR injury, which has potentially important implications for the future design of antiplatelet agents that can reduce microvascular dysfunction and inflammation.

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Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps

Cited by 71 publications

References 59 publications

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

Thromboinflammatory Functions of Platelets in Ischemia–Reperfusion Injury and Its Dysregulation in Diabetes

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