ANGIOGENIC INHIBITION OF SPINORPHIN , A POTENT ANALGESIC AND ANTIINFLAMMATORY SUBSTANCE

血管生成是新血管的形成，对于组织发育、再生和重塑至关重要。血管生成在实体瘤的生长和转移、糖尿病视网膜病变、类风湿性关节炎和银屑病等多种病理过程中也起着重要作用。血管生成的抑制导致这些疾病的抑制。另一方面，我们在人脊髓液中发现了一种对内源性阿片肽--脑啡肽的降解蛋白酶具有抑制活性的小肽，并从牛脊髓中纯化得到了一种新的小肽，命名为Spinorphin。Spinorphin是由七个氨基酸残基组成的肽，LVVYPWT。Spinorphin具有明显的抑制脑啡肽降解酶的活性，并具有镇痛作用，同时还具有趋化性、O_2产生和胞吐等炎症反应 ...更多信息 .首先，我们用鸡胚绒毛尿囊膜（CAM）检测其抗血管生成活性。Spinorphin有效抑制血管生成，呈剂量依赖性。这种活性增加，同时加入氨肽酶抑制剂，leuhistin，因为spinorphin被降解的氨肽酶在CAM测定。使用内皮细胞检查这种抑制的机制。该化合物不抑制牛肺动脉内皮（BPAE）细胞的增殖或管形成。先前，spinorphin被报道抑制缓激肽诱导的小鼠伤害性屈肌反应。这表明Spinorphin可能与缓激肽受体结合。我们研究了缓激肽拮抗剂的抗血管生成活性，它们显示出对CAM中血管生成的有效抑制。然而，spinorphin不抑制缓激肽与缓激肽受体的结合。此外，大鼠脊髓中可能存在一种特异性的Spinorphin受体。相反，血管紧张素转换酶（ACE）或氨肽酶（AP）的一些抑制剂抑制CAM中的血管生成。由于Spinorphin抑制ACE和AP的酶活性，因此Spinorphin的抗血管生成活性可能依赖于其酶调节。少

Angiogenesis is the formation of new blood vessels and is essential for tissue development, regeneration and remodeling. Angiogenesis also plays an important role in many pathological processes, such as growth and metastasis of solid tumor, diabetic retinopathy, rheumatoid arthritis and psoriasis. The inhibition of angiogenesis results in suppression of these diseases. On the other hand, we previously found a small peptide with inhibiting activity against proteases that degraded endogenous opioid peptide, enkephalin in human spinal fluid and purified it named as spinorphin from bovine spinal cord. Spinorphin is a peptide that consists seven amino acid residues, LVVYPWT. Spinorphin potently inhibited enkephalin-degrading enzymes and exhibited analgesic activity in mice and inflammatory responses such as chemotaxis, O_2-generation and exocytosis by human polymorphonuclear nutrophils.In this study, we investigated the antiangiogenic activity of spinorphin using in vivo and in vitro assays … More . First we examined its antiangiogenic activity using a chick embryo chorioallantoic membrane (CAM). Spinorphin potently inhibited angiogenesis, dose-dependently. This activity increased by simultaneous addition of an aminopeptidase inhibitor, leuhistin since spinorphin was degraded by aminopeptidase in CAM assay. The mechanism of this inhibition was examined using endothelial cells. This compound did not inhibit proliferation or tube formation of bovine pulmonary artcrial endothelial (BPAE)cells. Previously, spinorphin was reported to inhibit bradykinin-induced nociceptive flexor responses in mice. This suggested that spinorphin may bind bradykinin receptors. We examined antiangiogenic activity of bradykinin antagonists and they showed potent inhibition of angiogenesis in CAM. However, spinorphin did not inhibit binding of bradykinin to bradykinin receptors. Moreover, a specific receptor for spinorphin was suggested to exist in rat spinal cord. In contrast, some inhibitors of angiotensin-converting enzyme (ACE) or aminopeptidase (AP) suppressed angiogenesis in CAM. As spinorphin inhibits enzyme activities of ACE and AP, antiangiogenic activity of spinorphin may depend on its enzyme regulation. Less