Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts
Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts
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DOI：
10.1016/j.ijcard.2014.02.041
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发表时间：
2014-05-01
影响因子：
3.5
通讯作者：
Chen, Yi-Jen
中科院分区：
文献类型：
--
作者：
Lee, Ting-Wei;Kao, Yu-Hsun;Chen, Yi-Jen
背景：晚期糖基化终产物受体(RAGE)信号通路在糖尿病心血管并发症中起重要作用。骨化三醇已被证明具有多种有益的心血管作用。本研究旨在探讨骨化三醇能否调节糖尿病大鼠心脏RAGE的表达，并探讨其可能的机制。方法：链脲佐菌素(65 mg/kg)诱导的糖尿病大鼠每日皮下注射骨化三醇150 ng/kg，连续4周。免疫印迹法检测心肌RAGE、肿瘤坏死因子-α、核因子-kappaB p65亚单位(P65)、kappa B抑制因子(I-kappa-BA)亚基、NADPH氧化酶亚基(NOX4和p22(Phox))、血管紧张素II 1型受体(AT1R)、转化生长因子-β1、转化生长因子-β受体I、总的及磷酸化的Smad2/3和ERK、基质金属蛋白酶2(MMP2)、金属蛋白酶组织抑制物2(TIMP2)和I型前胶原蛋白的表达。结果：糖尿病大鼠心脏RAGE、肿瘤坏死因子-α、p22phx、AT1R和转化生长因子-1β的表达均高于对照组。在用骨化三醇治疗的糖尿病大鼠中，这种作用显著减弱。骨化三醇治疗的糖尿病心脏也比糖尿病心脏表达更少的p-Smad2/3和p-ERK信号。此外，糖尿病心脏MMP2和I型前胶原表达增加，TIMP2表达减少。结论：骨化三醇减轻糖尿病大鼠RAGE和纤维化的作用可能与其调节AT1R及抗炎、抗氧化作用有关。因此，骨化三醇可以减轻糖尿病心肌病变。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
Background: 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.Methods: 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-alpha, p65 subunit of NF-kappa B (p65), a subunit of inhibitor of kappa B (I kappa Ba), subunits of NADPH oxidase (NOX4 and p22(phox)), angiotensin II type 1 receptor (AT1R), TGF-beta 1, TGF-beta receptor I, total and phosphorylated SMAD2/3 and ERK, matrix metalloproteinases 2 (MMP2), tissue inhibitors of metalloproteinases 2 (TIMP2) and procollagen I.Results: As compared to control, diabetic rats had increased expressions of cardiac RAGE, TNF-alpha, p22phox, AT1R, and TGF-beta 1, 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.Conclusions: 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. (c) 2014 Elsevier Ireland Ltd. All rights reserved.