Mitogen-activated protein kinases (MAPKs) are expressed in platelets and are activated downstream of physiological agonists. Pharmacological and genetic evidence indicate that MAPKs play a significant role in hemostasis and thrombosis, but it is not well understood how MAPKs are activated upon platelet stimulation. Here, we show that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, is expressed in both human and murine platelets. ASK1 is rapidly and robustly activated upon platelet stimulation by physiological agonists. Disruption of ( ) resulted in a marked functional defect in platelets. platelets showed an impaired agonist-induced integrin αβ activation and platelet aggregation. Although there was no difference in Ca rise, platelet granule secretion and thromboxane A (TxA) generation were significantly attenuated in platelets. The defective granule secretion observed in platelets was a consequence of impaired TxA generation. Biochemical studies showed that platelet agonists failed to activate p38 MAPK in platelets. On the contrary, activation of c-Jun-terminal kinases and extracellular signal-regulated kinase 1/2 MAPKs was augmented in platelets. The defect in p38 MAPK results in failed phosphorylation of cPLA in platelets and impaired platelet aggregate formation under flow. The absence of Ask1 renders mice defective in hemostasis as assessed by prolonged tail-bleeding times. Deletion of also reduces thrombosis as assessed by delayed vessel occlusion of carotid artery after FeCl-induced injury and protects against collagen/epinephrine-induced pulmonary thromboembolism. These results suggest that the platelet Ask1 plays an important role in regulation of hemostasis and thrombosis.
The aim of this study was to assess the Activities of Daily Living (ADL) in patients with Hunter syndrome (mucopolysaccharidosis II; MPS II) using a newly designed ADL questionnaire. We applied the questionnaire to evaluate clinical phenotypes and therapeutic efficacies of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). We also explored early signs and symptoms to make early diagnosis feasible.
We devised a new ADL questionnaire with three domains: “Movement,” “Movement with Cognition,” and “Cognition.” Each domain has four subcategories rated on a 5-point scale based on level of assistance. We also scored signs and symptoms unique to MPS by 12 subcategories (five points per category), providing 60 points in total. The questionnaire was first administered to 138 healthy Japanese controls (0.33 – 50 years), and successively, to 74 Japanese patients with Hunter syndrome (4 – 49 years). The patient cohort consisted of 51 severe and 23 attenuated phenotypes; 20 patients treated with HSCT, 23 patients treated early with ERT (≤ 8 years), and 25 patients treated late with ERT (> 8 years), and 4 untreated patients. Among 18 severe phenotypic patients treated by HSCT, 10 were designated as early HSCT (≤ 5 years), while 8 were designated as late HSCT (> 5 years).
Scores from patients with severe phenotypes were lower than controls and attenuated phenotypes in all categories. Among patients with severe phenotypes, there was a trend that HSCT provides a higher ADL score than early ERT, and there was a significant difference in ADL scores between late ERT and HSCT groups. Early ERT and early HSCT provided a higher score than late ERT and late HSCT, respectively.
In conclusion, we have evaluated the feasibility of a new questionnaire in control population and patients with Hunter syndrome, leading to a novel evaluation method for clinical phenotypes and therapeutic efficacy. Early treatment with HSCT provides a better consequence in ADL of patients.
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