Hubei Key Laboratory of Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning 437100, China.
Acta Pharmacol Sin. 2018 Feb;39(2):195-204. doi: 10.1038/aps.2017.92. Epub 2017 Sep 14.
Cardiac fibrosis is considered the initial change of diabetic cardiomyopathy (DCM). We have shown that curcumin alleviates collagen deposition in DCM, but the mechanism remains unknown. In this study we sought to investigate the effects of curcumin on cardiac fibrosis in vivo and in vitro and to elucidate the underlying mechanisms. Experimental diabetes was induced in rats by injection of low-dose streptozotocin (STZ) combined with high energy diet. The rats were orally treated with curcumin (300 mg·kg·d) for 16 weeks. Curcumin administration significantly suppressed the deposition of type I and type III collagens in the heart tissues of diabetic rats, accompanied by markedly reduced TGF-β1 production, suppressed TβR II levels and Smad2/3 phosphorylation, and increased Smad7 expression. Similar effects were observed in human cardiac fibroblasts exposed to high glucose (HG, 30 mmol/L) or exogenous TGF-β1 (5 ng/mL). Furthermore, TGF-β1 or HG treatment significantly increased the phosphorylation levels of AMPK and p38 MAPK in the fibroblasts. Application of curcumin (25 μmol/L) inhibited TGF-β1- or HG-induced AMPK/p38 MAPK activation and suppressed collagen synthesis in the fibroblasts. These effects were similar to those of the AMPK inhibitor compound C (10 μmol/L) but opposite to the effects of the AMPK activator metformin (2 mmol/L) in the fibroblasts. Our results demonstrate that curcumin suppresses diabetes-associated collagen synthesis in rat myocardium not only by inhibiting TGF-β1 production and canonical Smad signaling but also by blocking the non-canonical AMPK/p38 MAPK pathway.
心脏纤维化被认为是糖尿病心肌病（DCM）的初始变化。我们已经表明，姜黄素减轻 DCM 中的胶原沉积，但机制尚不清楚。在这项研究中，我们旨在研究姜黄素在体内和体外对心脏纤维化的影响，并阐明潜在的机制。通过注射低剂量链脲佐菌素（STZ）结合高能量饮食在大鼠中诱导实验性糖尿病。大鼠口服姜黄素（300mg·kg·d）治疗 16 周。姜黄素给药显著抑制糖尿病大鼠心脏组织中 I 型和 III 型胶原的沉积，同时 TGF-β1 的产生明显减少，TβR II 水平和 Smad2/3 磷酸化受到抑制，Smad7 表达增加。在暴露于高葡萄糖（HG，30mmol/L）或外源性 TGF-β1（5ng/mL）的人心肌成纤维细胞中观察到类似的效果。此外，TGF-β1 或 HG 处理显著增加了成纤维细胞中 AMPK 和 p38 MAPK 的磷酸化水平。应用姜黄素（25μmol/L）抑制 TGF-β1 或 HG 诱导的 AMPK/p38 MAPK 激活，并抑制成纤维细胞中的胶原合成。这些作用与 AMPK 抑制剂化合物 C（10μmol/L）相似，但与 AMPK 激活剂二甲双胍（2mmol/L）在成纤维细胞中的作用相反。我们的结果表明，姜黄素不仅通过抑制 TGF-β1 的产生和经典 Smad 信号通路，而且通过阻断非经典 AMPK/p38 MAPK 通路来抑制糖尿病相关的胶原合成。
