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INTRODUCTION: Several reports have demonstrated the surgical treatment strategy for patients with dialysis-associated spondylosis in the cervical spine (CDAS) with destructive spondyloarthropathy (DSA). However, studies focusing on the clinical outcome of patients with CDAS without DSA remain scarce. We aimed to review the treatment strategy of patients with CDAS but without DSA. METHODS: The clinical data and surgical records of consecutive patients with CDAS without DSA (n = 9; D-group) and cervical spondylotic myelopathy (CSM) (n = 30; C-group) who underwent modified double-door laminoplasty(DDL) were reviewed retrospectively. We investigated four radiologic factors in the pre-and postoperative periods that have been reported to be the risk factors for worsening of clinical symptoms in various studies and examined statistical comparison between the D and C groups. RESULTS: In the D group, the pre- versus postoperative C2-C7 sagittal angles were not significantly different, and only two patients (22%) had kyphosis postoperatively. There was a significant difference in the pre- and postoperative C2-C7 angles in the two groups (P = 0.031). Regarding the change in segmental alignment, the local open angle increased at the C4/C5 level in the D group. Also there was a significant difference in the local angles between the two groups at C4/5 and C5/6 (P = 0.00038, and 0.037), suggesting that postoperative segmental mobility at C4/5 and C5/6 was higher in the D group than in the C group. CONCLUSIONS: In the present study, DDL in patients with CDAS without DSA did not adversely affect the postoperative alignment and stability compared with CSM patients with CSM. However, patients in the D group may have a chance to develop DSA change at the C4/5 level in the future, and careful long-term follow-up is warranted.
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OBJECTIVE: Protease-activated receptor-1 (PAR1) mediates the thrombin-induced proliferation and hypertrophy of vascular smooth muscle cells. A role of Rac1 in the regulation of PAR1 expression was investigated. METHODS AND RESULTS: Treatment with simvastatin, a hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, for 24 hours attenuated the transient [Ca2+]i elevation induced by thrombin. Immunofluorescence staining revealed that simvastatin decreased the surface expression of PAR1 in a manner dependent on protein geranylgeranylation. Introduction of a Rac1/Cdc42 inhibitory fragment but not a RhoA inhibitory fragment using a cell-penetrating peptide also attenuated the response to thrombin and decreased the surface expression of PAR1. Finally, downregulation of Rac1, but not RhoA, using an RNA interference technique attenuated the thrombin-induced [Ca2+]i elevation. However, the level of PAR1 mRNA and the total amount of PAR1 protein remained unchanged. CONCLUSIONS: Here, we provide for the first time 3 lines of evidence that Rac1 plays a critical role in maintaining the surface expression of PAR1 and the responsiveness to thrombin in vascular smooth muscle cells. Rac1 is suggested to regulate the constitutive trafficking of PAR1 and thereby regulate the surface expression of PAR1.
Asunto(s)
Músculo Liso Vascular/metabolismo , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Trombina/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Animales , Aorta/citología , Calcio/metabolismo , Células Cultivadas , Vasos Coronarios/citología , Regulación hacia Abajo/efectos de los fármacos , Expresión Génica , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Prenilación de Proteína , ARN Mensajero/análisis , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Simvastatina/farmacología , Trombina/farmacología , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
The level of receptors expressed on the cell surface determines the cellular responsiveness to agonists. Proteinase-activated receptors (PARs) have been reported to be either up-regulated or down-regulated in response to various types of stimulation and pathological situations. In addition, the transcriptional regulation plays a major role in the alteration of the expression of PARs under pathological conditions, while post-translational mechanisms such as phosphorylation, arresting-binding, internalization, and lysosomal degradation, which desensitize activated PARs and terminate intracellular signaling, also play an important role in regulating the expression of PARs and the cellular responsiveness to the agonists. Elucidating the mechanisms related to the expression of PARs is a critical step to understand the pathophysiology of various diseases and establish new therapeutic strategies. However, the molecular mechanism regulating the expression of PARs still remains to be elucidated. This minireview discusses our current understanding of the mechanisms regulating the expression of PARs. The transcription factors and the regulatory elements in the promoter regions, and the proteins that interact with the receptors and thereby regulate their trafficking and desensitization are the main problems that need to be elucidated.