Kaur Harkiran, Chen Shali, Xin Xiping, Chiu Jane, Khan Zia A, Chakrabarti Subrata
Department of Pathology, 4011 Dental Sciences Building, University of Western Ontario, London, Ontario, Canada.
Diabetes. 2006 Nov;55(11):3104-11. doi: 10.2337/db06-0519.
Increased fibronectin expression is a key feature of diabetic angiopathy. We have previously shown that nuclear factor-kappaB (NF-kappaB) mediates fibronectin expression in endothelial cells and in organs affected by diabetes complications. p300, a transcription coactivator, may regulate NF-kappaB activity via poly(ADP-ribose) polymerase (PARP) activation. Hence, we examined the role of p300 in fibronectin expression in diabetes. High glucose induced fibronectin expression in the endothelial cells, which was associated with increased p300, PARP activity, and NF-kappaB activation. This p300 alteration is mediated by mitogen-activated protein kinase and protein kinase C and B. We then used p300 small interfering RNA (siRNA) and showed decreased fibronectin and PARP expression, as well as NF-kappaB activation, in the endothelial cells. Examination of the heart tissues of streptozotocin-induced diabetic mice revealed increased fibronectin and p300 mRNA. Intravenous injection of p300 siRNA resulted in decreased p300 levels and normalized fibronectin expression in the heart. We further investigated retinal tissues from streptozotocin-induced diabetic rats treated with intravitreal p300 siRNA injection. Similar to the heart, p300 siRNA inhibited fibronectin expression in the retina of the diabetic animals. These results indicate that transcriptional coactivator p300 may regulate fibronectin expression via PARP and NF-kappaB activation in diabetes.
纤连蛋白表达增加是糖尿病血管病变的一个关键特征。我们之前已经表明，核因子-κB（NF-κB）介导内皮细胞以及受糖尿病并发症影响的器官中纤连蛋白的表达。转录共激活因子p300可能通过聚（ADP-核糖）聚合酶（PARP）激活来调节NF-κB活性。因此，我们研究了p300在糖尿病中纤连蛋白表达中的作用。高糖诱导内皮细胞中纤连蛋白表达增加，这与p300、PARP活性以及NF-κB激活增加有关。这种p300的改变是由丝裂原活化蛋白激酶以及蛋白激酶C和B介导的。然后我们使用p300小干扰RNA（siRNA），结果显示内皮细胞中纤连蛋白和PARP表达降低，以及NF-κB激活减少。对链脲佐菌素诱导的糖尿病小鼠心脏组织的检查显示纤连蛋白和p300 mRNA增加。静脉注射p300 siRNA导致p300水平降低，心脏中纤连蛋白表达恢复正常。我们进一步研究了玻璃体内注射p300 siRNA治疗的链脲佐菌素诱导的糖尿病大鼠的视网膜组织。与心脏相似，p300 siRNA抑制糖尿病动物视网膜中纤连蛋白的表达。这些结果表明，转录共激活因子p300可能在糖尿病中通过PARP和NF-κB激活来调节纤连蛋白的表达。
