Chang Wei-Ting, Cheng Juei-Tang, Chen Zhih-Cherng
Department of Cardiology, Chi Mei Medical Center, 901, Zhonghua Road, Yongkang District, Tainan, Taiwan, ROC.
Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.
Cardiovasc Diabetol. 2016 Aug 12;15(1):113. doi: 10.1186/s12933-016-0430-5.
BACKGROUND: Despite the known risk of diabetes-induced cardiac fibrosis, less is known about whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Peroxisome proliferator-activated receptor δ (PPARδ), a versatile regulator of metabolic homeostasis, may be a potential therapeutic target. Herein we investigated the effectiveness of telmisartan, a unique angiotensin receptor blocker that increases PPARδ expression, in improving left ventricular remodeling in diabetic humans and rats. METHODS: In this longitudinal, prospective study, we enrolled 15 diabetic patients receiving telmisartan (20 mg/day) for 12 weeks. After treatment, strain was measured and compared with the baseline value. Using streptozotocin to induce type 1 diabetes rat model, we measured PPARδ expression and downstream targets. RESULTS: After treatment with telmisartan, both longitudinal and circumferential strains improved in diabetic patients. Compared with that of controls, the diabetic rat heart developed significant fibrosis, which markedly decreased after treatment with telmisartan (30 mg/kg/day, orally) for 7 days. After incubation with 30 mM glucose, rat cardiomyocytes showed a significant down-regulation of PPARδ. Interestingly, the increased expression of fibrosis-associated proteins, including signal transducer and activator of transcription 3 (STAT3) was attenuated by the co-incubation of GW0742, a PPARδ agonist. By knockdown or inhibition of STAT3, the hyperglycemia related high expression of fibrosis associated targets was reversed. Independent from the hyperglycemic incubation, STAT3 over-expression led to similar results. Conversely, in the presence of GSK0660, a PPARδ inhibitor, the protective effects of telmisartan were diminished. CONCLUSION: Telmisartan improved the hyperglycemia-induced cardiac fibrosis through the PPARδ/STAT3 pathway. Graphical abstract Summary of the mechanism of telmisartan's effect on the suppression of hyperglycemia-induced cardiac fibrosis through PPARδ instead of the AMPK pathway. PPARδ peroxisome proliferator-activated receptor δ, STAT3 signal transducer and activator of transcription 3, CTGF connective tissue growth factor, MMP9 matrix metallopeptidase 9.
背景：尽管已知糖尿病会引发心脏纤维化，但对于糖尿病是否会导致独立于冠状动脉粥样硬化之外的心脏表型改变，我们了解得较少。过氧化物酶体增殖物激活受体δ（PPARδ）作为代谢稳态的多功能调节因子，可能是一个潜在的治疗靶点。在此，我们研究了替米沙坦（一种可增加PPARδ表达的独特血管紧张素受体阻滞剂）在改善糖尿病患者和大鼠左心室重构方面的有效性。 方法：在这项纵向前瞻性研究中，我们纳入了15名接受替米沙坦（20毫克/天）治疗12周的糖尿病患者。治疗后，测量应变并与基线值进行比较。使用链脲佐菌素诱导1型糖尿病大鼠模型，我们测量了PPARδ表达及其下游靶点。 结果：替米沙坦治疗后，糖尿病患者的纵向和圆周应变均有所改善。与对照组相比，糖尿病大鼠心脏出现了明显的纤维化，在用替米沙坦（30毫克/千克/天，口服）治疗7天后，纤维化明显减少。在与30毫摩尔葡萄糖孵育后，大鼠心肌细胞中PPARδ显著下调。有趣的是，PPARδ激动剂GW0742共同孵育可减弱包括信号转导和转录激活因子3（STAT3）在内的纤维化相关蛋白表达的增加。通过敲低或抑制STAT3，可逆转高血糖相关的纤维化相关靶点的高表达。独立于高血糖孵育之外，STAT3过表达也导致了类似结果。相反，在存在PPARδ抑制剂GSK0660的情况下，替米沙坦的保护作用减弱。 结论：替米沙坦通过PPARδ/STAT3途径改善高血糖诱导的心脏纤维化。图形摘要 替米沙坦通过PPARδ而非AMPK途径抑制高血糖诱导的心脏纤维化的作用机制总结。PPARδ过氧化物酶体增殖物激活受体δ，STAT3信号转导和转录激活因子3，CTGF结缔组织生长因子，MMP9基质金属蛋白酶9
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