The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation
The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation
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DOI：
10.1172/jci200419252
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发表时间：
2004-03-01
影响因子：
15.9
通讯作者：
Van Geet, C
中科院分区：
文献类型：
--
作者：
Freson, K;Hashimoto, H;Van Geet, C
垂体腺苷酸环化酶激活多肽（PACAP）是血管活性肠肽/促胰液素/胰高血糖素超家族的神经肽。对两名部分18 p三体相关患者的研究显示，PACAP基因有三个拷贝，血浆中PACAP浓度升高。患者患有严重的智力低下，有出血倾向，伴有轻度血小板减少症，其成纤维细胞显示PACAP mRNA水平升高。血小板和成纤维细胞中的PACAP受体（血管活性肠肽/垂体腺苷酸环化酶激活肽受体1 [VPAC 1]）与腺苷酸环化酶激活偶联。因此，我们发现患者血小板和成纤维细胞中基础cAMP水平增加，为这些患者血小板聚集减少提供了基础。小鼠巨核细胞特异性转基因过表达PACAP相应地增加了血小板释放PACAP，减少了血小板活化，延长了尾部出血时间。相反，PACAP拮抗剂PACAP（6-38）或单克隆PACAP抗体增强胶原诱导的正常人血小板聚集，并且在PACAP敲除小鼠中，发现血小板对胶原的敏感性增加。我们的研究提示了通过分别给予PACAP模拟物或抑制剂来控制动脉血栓形成或出血的治疗潜力。
The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide of the vasoactive intestinal peptide/secretin/glucagon superfamily. Studies in two related patients with a partial trisomy 18p revealed three copies of the PACAP gene and elevated PACAP concentrations in plasma. The patients suffer from severe mental retardation and have a bleeding tendency with mild thrombocytopenia, and their fibroblasts show increased PACAP mRNA levels. The PACAP receptor (vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor 1 [VPAC1]) in platelets and fibroblasts is coupled to adenylyl cyclase activation. Accordingly, we found increased basal cAMP levels in patients' platelets and fibroblasts, providing a basis for the reduced platelet aggregation in these patients. Megakaryocyte-specific transgenic overexpression of PACAP in mice correspondingly increased PACAP release from platelets, reduced platelet activation, and prolonged the tail bleeding time. In contrast, the PACAP antagonist PACAP(6-38) or a monoclonal PACAP antibody enhanced the collagen-induced aggregation of normal human platelets, and in PACAP knockout mice, an increased platelet sensitivity toward collagen was found. Thus, we found that PACAP modulates platelet function and demonstrated what we believe to be the first hemostatic defect associated with PACAP overexpression; our study suggests the therapeutic potential to manage arterial thrombosis or bleeding by administration of PACAP mimetics or inhibitors, respectively.