Lee Ting-Wei, Kao Yu-Hsun, Lee Ting-I, Chang Chun-Jen, Lien Gi-Shih, Chen Yi-Jen
Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Int J Cardiol. 2014 May 1;173(2):236-41. doi: 10.1016/j.ijcard.2014.02.041. Epub 2014 Feb 28.
Receptor for advanced glycation end products (RAGE) signaling pathway plays a vital role in diabetic cardiovascular complications. Calcitriol has been shown to exert various beneficial cardiovascular effects. The purpose of this study is to determine whether calcitriol can modulate RAGE expression, and study the potential mechanisms in diabetic hearts.
Streptozotocin (65 mg/kg, intraperitoneal injection once) induced diabetic rats were treated with or without subcutaneous injections of calcitriol at a dose of 150 ng/kg/day for 4 weeks. Western blot was used to evaluate protein expressions of myocardial RAGE, TNF-α, p65 subunit of NF-κB (p65), α subunit of inhibitor of κB (IκBα), subunits of NADPH oxidase (NOX4 and p22(phox)), angiotensin II type 1 receptor (AT1R), TGF-β1, TGF-β receptor I, total and phosphorylated SMAD2/3 and ERK, matrix metalloproteinases 2 (MMP2), tissue inhibitors of metalloproteinases 2 (TIMP2) and procollagen I.
As compared to control, diabetic rats had increased expressions of cardiac RAGE, TNF-α, p22(phox), AT1R, and TGF-β1, which were significantly attenuated in the diabetic rats treated with calcitriol. Calcitriol-treated diabetic hearts also had lesser expressions of p-SMAD2/3 and p-ERK signaling than those of diabetic hearts. Moreover, diabetic hearts had increased expressions of MMP2 and procollagen I and decreased TIMP2. However, calcitriol reverted the diabetic effects in procollagen I but not in MMP2 or TIMP2.
Calcitriol decreased diabetic effects on RAGE and fibrosis, which may be caused by its modulation on AT1R and the anti-inflammatory and antioxidative potentials. Therefore, calcitriol may attenuate diabetic cardiomyopathy.
晚期糖基化终末产物受体（RAGE）信号通路在糖尿病心血管并发症中起关键作用。已证明骨化三醇具有多种有益的心血管作用。本研究的目的是确定骨化三醇是否能调节RAGE表达，并研究其在糖尿病心脏中的潜在机制。
用链脲佐菌素（65mg/kg，腹腔注射一次）诱导糖尿病大鼠，对其进行皮下注射骨化三醇（剂量为150ng/kg/天）或不注射处理，持续4周。采用蛋白质印迹法评估心肌RAGE、肿瘤坏死因子-α（TNF-α）、核因子κB（NF-κB）的p65亚基（p65）、κB抑制蛋白（IκBα）的α亚基、烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX4和p22（phox））的亚基、血管紧张素II 1型受体（AT1R）、转化生长因子-β1（TGF-β1）、TGF-β受体I、总SMAD2/3和磷酸化SMAD2/3以及细胞外信号调节激酶（ERK）、基质金属蛋白酶2（MMP2）、金属蛋白酶组织抑制剂2（TIMP2）和I型前胶原的蛋白表达。
与对照组相比，糖尿病大鼠心脏中RAGE、TNF-α、p22（phox）、AT1R和TGF-β1的表达增加，但在用骨化三醇治疗的糖尿病大鼠中这些表达显著减弱。与糖尿病心脏相比，用骨化三醇治疗的糖尿病心脏中p-SMAD2/3和p-ERK信号的表达也较少。此外，糖尿病心脏中MMP2和I型前胶原的表达增加，TIMP2表达减少。然而，骨化三醇可逆转糖尿病对I型前胶原的影响，但对MMP2或TIMP2无此作用。
骨化三醇可减轻糖尿病对RAGE和纤维化的影响，这可能是由于其对AT1R的调节作用以及抗炎和抗氧化作用。因此，骨化三醇可能减轻糖尿病性心肌病。
