Fukuda Gen, Khan Zia A, Barbin Yousef P, Farhangkhoee Hana, Tilton Ronald G, Chakrabarti Subrata
Department of Pathology, University of Western Ontario, London, ON, Canada.
Diabetes Metab Res Rev. 2005 Jul-Aug;21(4):367-75. doi: 10.1002/dmrr.527.
Smooth muscle cells proliferation and extracellular matrix (ECM) protein deposition are key features of diabetic macroangiopathy. In the present study, we have studied the role of endothelin(A) (ET(A)) receptor, the predominant receptor on smooth muscle cells, in diabetes-induced vascular hypertrophy and remodeling.
Streptozotocin-induced diabetic rats were administrated a selective ET(A) receptor antagonist, TBC3214, for 26 weeks. Following treatment, aortas were harvested and subjected to gene expression and morphometric analyses. We quantified fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1) expression as indicators of increased ECM protein synthesis. ET-1, ET-3, transforming growth factor-beta1 (TGF-beta1) and angiotensinogen mRNA levels were measured to elucidate genes involved in FN expression. We have investigated an embryonic splice variant of FN, oncofetal FN, and nonmuscle myosin heavy chain (SMemb) as vascular remodeling indicators.
Our results show that diabetes leads to upregulation of FN, PAI-1, ET-1, ET-3, TGF-beta1 and angiotensinogen mRNA levels in association with increased medial thickness. Immunohistochemical analyses revealed concurrent protein level changes. Diabetes also upregulated oncofetal FN and SMemb mRNA levels. Treatment with TBC3214 attenuated the mRNA levels of several genes and prevented increased medial thickness.
These results indicate that diabetes-induced vascular hypertrophy and remodeling is associated with reexpression of embryonic forms of FN and myosin heavy chain. Such changes are ET-dependent and may be mediated via TGF-beta1 and angiotensin.
平滑肌细胞增殖和细胞外基质（ECM）蛋白沉积是糖尿病大血管病变的关键特征。在本研究中，我们研究了平滑肌细胞上的主要受体内皮素（A）（ET（A））受体在糖尿病诱导的血管肥大和重塑中的作用。
给链脲佐菌素诱导的糖尿病大鼠施用选择性ET（A）受体拮抗剂TBC3214，持续26周。治疗后，采集主动脉并进行基因表达和形态计量分析。我们将纤连蛋白（FN）和纤溶酶原激活物抑制剂-1（PAI-1）的表达定量作为ECM蛋白合成增加的指标。测量ET-1、ET-3、转化生长因子-β1（TGF-β1）和血管紧张素原mRNA水平，以阐明参与FN表达的基因。我们研究了FN的一种胚胎剪接变体、癌胚FN和非肌肉肌球蛋白重链（SMemb）作为血管重塑指标。
我们的结果表明，糖尿病导致FN、PAI-1、ET-1、ET-3、TGF-β1和血管紧张素原mRNA水平上调，同时中膜厚度增加。免疫组织化学分析显示蛋白质水平同时发生变化。糖尿病还上调了癌胚FN和SMemb mRNA水平。用TBC3214治疗可降低几种基因的mRNA水平，并防止中膜厚度增加。
这些结果表明，糖尿病诱导的血管肥大和重塑与FN和肌球蛋白重链胚胎形式的重新表达有关。这种变化是ET依赖性的，可能通过TGF-β1和血管紧张素介导。
