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1.
Arterioscler Thromb Vasc Biol ; 43(8): 1494-1509, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37381987

RESUMO

BACKGROUND: MAGT1 (magnesium transporter 1) is a subunit of the oligosaccharide protein complex with thiol-disulfide oxidoreductase activity, supporting the process of N-glycosylation. MAGT1 deficiency was detected in human patients with X-linked immunodeficiency with magnesium defect syndrome and congenital disorders of glycosylation, resulting in decreased cation responses in lymphocytes, thereby inhibiting the immune response against viral infections. Curative hematopoietic stem cell transplantation of patients with X-linked immunodeficiency with magnesium defect causes fatal bleeding and thrombotic complications. METHODS: We studied the role of MAGT1 deficiency in platelet function in relation to arterial thrombosis and hemostasis using several in vitro experimental settings and in vivo models of arterial thrombosis and transient middle cerebral artery occlusion model of ischemic stroke. RESULTS: MAGT1-deficient mice (Magt1-/y) displayed accelerated occlusive arterial thrombus formation in vivo, a shortened bleeding time, and profound brain damage upon focal cerebral ischemia. These defects resulted in increased calcium influx and enhanced second wave mediator release, which further reinforced platelet reactivity and aggregation responses. Supplementation of MgCl2 or pharmacological blockade of TRPC6 (transient receptor potential cation channel, subfamily C, member 6) channel, but not inhibition of store-operated calcium entry, normalized the aggregation responses of Magt1-/y platelets to the control level. GP (glycoprotein) VI activation of Magt1-/y platelets resulted in hyperphosphorylation of Syk (spleen tyrosine kinase), LAT (linker for activation of T cells), and PLC (phospholipase C) γ2, whereas the inhibitory loop regulated by PKC (protein kinase C) was impaired. A hyperaggregation response to the GPVI agonist was confirmed in human platelets isolated from a MAGT1-deficient (X-linked immunodeficiency with magnesium defect) patient. Haploinsufficiency of TRPC6 in Magt1-/y mice could normalize GPVI signaling, platelet aggregation, and thrombus formation in vivo. CONCLUSIONS: These results suggest that MAGT1 and TRPC6 are functionally linked. Therefore, deficiency or impaired functionality of MAGT1 could be a potential risk factor for arterial thrombosis and stroke.


Assuntos
Proteínas de Transporte de Cátions , Homeostase , Infarto da Artéria Cerebral Média , AVC Isquêmico , Trombose , Animais , Humanos , Camundongos , Plaquetas/metabolismo , Cálcio/metabolismo , Cátions/metabolismo , AVC Isquêmico/genética , AVC Isquêmico/complicações , AVC Isquêmico/metabolismo , Magnésio/metabolismo , Ativação Plaquetária , Agregação Plaquetária , Glicoproteínas da Membrana de Plaquetas/metabolismo , Trombose/genética , Trombose/metabolismo , Canal de Cátion TRPC6/metabolismo , Proteínas de Transporte de Cátions/deficiência
2.
Nat Commun ; 7: 11097, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-27020697

RESUMO

Mg(2+) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg(2+)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7(fl/fl-Pf4Cre)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7(fl/fl-Pf4Cre) MKs, which is rescued by Mg(2+) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.


Assuntos
Citoesqueleto/metabolismo , Homeostase , Magnésio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Trombopoese , Animais , Plaquetas/metabolismo , Humanos , Megacariócitos/metabolismo , Camundongos , Proteínas Mutantes/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Canais de Cátion TRPM/deficiência , Trombocitopenia/metabolismo , Trombocitopenia/patologia
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