Peroxisome proliferator-activated receptor-γ activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor
Peroxisome proliferator-activated receptor-γ activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor
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DOI：
10.1007/s00395-009-0071-x
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发表时间：
2010-05-01
影响因子：
9.5
通讯作者：
Kim, Jae-Hyung
中科院分区：
文献类型：
--
作者：
Ihm, Sang-Hyun;Chang, Kiyuk;Kim, Jae-Hyung
晚期糖基化终末产物 (RAGE) 和结缔组织生长因子 (CTGF) 受体在糖尿病心肌纤维化中发挥关键作用，据报道过氧化物酶体增殖物激活受体-γ (PPAR-γ) 激活可减少 RAGE 和 CTGF 表达。本研究调查了 PPAR-γ 激动剂罗格列酮对 2 型糖尿病 (T2D) 大鼠心肌 RAGE 和 CTGF 表达、心脏纤维化程度和左心室 (LV) 舒张功能的影响。 20 周大的 T2D 大鼠被随机接受 20 周的罗格列酮 (20 mg/kg) 或生理盐水治疗（每组 n = 10）。在随机分组前（20 周）和研究完成时（40 周）进行系列超声心动图检查。通过天狼星红染色、实时逆转录酶偶联聚合酶链反应 (RT-PCR) 和免疫印迹分别评估先前成像的心脏中的纤维化程度以及 RAGE 和 CTGF 表达。后者的评估结果通过免疫组织化学染色进一步验证。罗格列酮治疗显着改善了连续超声心动图评估中的 E/A 比，并降低了左心室胶原体积分数，如天狼星红染色所示。罗格列酮治疗大鼠心肌组织的实时 RT-PCR 和免疫印迹显示，与生理盐水治疗的 T2D 大鼠相比，RAGE 和 CTGF mRNA 和蛋白信号减少，这与 T2D 大鼠心脏中心肌 RAGE 和 CTGF 染色比例的降低一致。通过连续超声心动图评估，PPAR-γ 激动剂治疗可减少心脏纤维化并改善左心室舒张功能障碍。抑制糖尿病心肌中 RAGE 和 CTGF 的表达似乎有助于罗格列酮的抗纤维化作用。这些结果支持 PPAR-γ 激动剂作为糖尿病心肌病抗纤维化药物的潜力。
Receptor for advanced glycation end products (RAGE) and connective tissue growth factor (CTGF) play a key role in diabetic myocardial fibrosis, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation has been reported to reduce RAGE and CTGF expression. This study investigated the effects of the PPAR-gamma agonist, rosiglitazone, on myocardial expression of RAGE and CTGF, extent of cardiac fibrosis, and left ventricular (LV) diastolic function in type 2 diabetic (T2D) rats. Twenty-week-old T2D rats were randomized to treatment with either 20 weeks of rosiglitazone (20 mg/kg) or saline (n = 10 in each group). Serial echocardiographic examinations were performed just before randomization (20 weeks) and at study completion (40 weeks). Fibrosis extent and RAGE and CTGF expression were assessed in previously imaged hearts by picrosirius red staining, and by real-time reverse transcriptase-coupled polymerase chain reaction (RT-PCR) and immunoblotting, respectively. Results of the latter assessments were further validated by immunohistochemical staining. Rosiglitazone treatment significantly improved E/A ratio in serial echocardiography assessment, and reduced LV collagen volume fraction as demonstrated by picrosirius red staining. Real-time RT-PCR and immunoblots of myocardial tissue from rosiglitazone-treated rats revealed reduced RAGE and CTGF mRNA and protein signals compared to those of saline-treated T2D rats, which were consistent with reduced proportions of myocardial RAGE and CTGF staining in the hearts of T2D rats. PPAR-gamma agonist therapy reduces cardiac fibrosis and improves LV diastolic dysfunction as assessed by serial echocardiographic imaging. Suppression of RAGE and CTGF expression in the diabetic myocardium appears to contribute to the antifibrotic effect of rosiglitazone. These results support the potential of PPAR-gamma agonists as antifibrotic agents in diabetic cardiomyopathy.