| 摘要: | 中文摘要
血管增生意指從已存在的微血管中長出新的血管，生理方面如胚胎發育、個體的成長、傷口癒合、女性的月經週期。病理方面如腫瘤生成、風濕性關節炎、糖尿病造成的視網膜病變都與血管增生有關。行政院衛生署針對台灣地區國人死亡原因的統計資料顯示，前五名分別是惡性腫瘤、腦血管疾病、心臟疾病、事故傷害、糖尿病。肺癌、肝癌、結腸直腸癌、女性乳癌、胃癌也分別佔據前五大癌症死亡的位置。從流行病學的角度上得知肥胖的病人容易罹患癌症如乳癌、結腸直腸癌、口腔癌(含口咽及下咽) 、子宮頸癌和其他血管增生相關疾病，風濕性關節炎、糖尿病造成的視網膜病變。但是目前對於肥胖和癌症之間的機制，仍然了解不清楚。
Resistin是由脂肪組織分泌之與胰島素阻抗性的形成有關，當給予anti-diabetic drug rosiglitazone會降低在血液中的resistin濃度，而給予食用高脂肪食物之肥胖小鼠和基因缺陷之小鼠 (ob/ob;db/db mice)，血液中resistin的濃度會上升。以腹腔注射的方式給予anti-resistin抗體會促進食用高脂肪食物之肥胖小鼠的血糖吸收和胰島素的利用，給予正常小鼠resistin則會破壞小鼠血糖耐受性和胰島素活性，因此resistin被認為是連接肥胖與糖尿病兩者的之一。
1990年初期從美國西南大毒蜥蜴的毒液中發現一些具有生物活性的，分別為helospectin、helodermin、exendin-3, 和exendin-4，前兩種也稱為exendin-1和exendin-2。Exendin-3是由39個胺基酸組成，分子量大小為4,200，與helospectin和helodermin的相似度分別為32和26% 和其他glucagon/VIP/secretin家族成員相比較，和secretin它的12 amino-terminal residues相似度為91%，和人類的glucagon like peptide-1 (GLP-1) 有50%的相似度，而對分離的天竺鼠的pancreatic acini作用上，3 mM的濃度可以增加細胞的cyclic 3’, 5’-adenosine monophosphate (cAMP) 高達80倍和9倍的amylase釋放。
本篇論文利用，人類臍靜脈內皮細胞 (HUVEC) 之capillary tube formation assay、migration assay和rat aorta tube formation assay等方法，結果顯示肥胖相關之resistin (23-42) 和exendin-3於HUVEC capillary tube formation assay具有抑制caplliary tube formation，並且隨著濃度的增加，抑制的能力上升。Resistin (23-42) 和exendin-3於Migration assay中抑制HUVEC移動的能力。血管內皮生長因子 (VEGF) 刺激HUVEC migration下，resistin (23-42) 和exendin-3的抑制作用並不影響。Aorta tube formation assay中，利用特殊的刀組和利用MTS/PMS 的比色測定法作為定量和測定內皮細胞生長的方法，結果亦顯示resistin (23-42) 和exendin-3抑制rat aorta tube formation。綜合以上結果，resistin (23-42) 和exendin-3可能參與調控血管生長，詳細的調控機制與其細胞內訊息傳遞之途徑則有待進一步研究。
Abstract
Angiogenesis the formation of new blood vessels out of pre-existing capillaries is a sequence of events that is of key importance in a broad array of physiologic and pathological processes. In physiologic conditions, such as embryonic development, wound healing, and the menstrual cycle, angiogenesis is necessary. In pathological conditions, such as cancer, rheumatoid arthritis, diabetic retinopathy, angiogenesis is also involved. The top five leading causes of death published by department of health, Taiwan, R.O.C. in 2001 are cancers, cardiovascular disease, heart disease, accident, and diabetes. Epidemic data show that obese patients have high risk for cancer in breast, colon, oral cavity, cervix and other angiogenesis dependent diseases. The pathological molecular mechanisms of cancer and obesity are not yet well-known. This study is aimed to uncover the relationships between cancer and obesity. Two obesity-associated factors, resistin (23-42) and exendin-3 were identified by their inhibitory effects on angiogenesis in the rat aorta tube formation assay. There were also found to inhibit HUVEC capillary tube formation and HUVEC migration assay in a concentration dependent manner. Our results indicate that resistin (23-42) and exendin-3 participate in the regulation of vascular growth. The underlying cellular mechanism is, however, still unknown and will be discussed and further studied. |
