Retinol-Binding Protein 4 Induces Cardiomyocyte Hypertrophy by Activating TLR4/MyD88 Pathway
Retinol-Binding Protein 4 Induces Cardiomyocyte Hypertrophy by Activating TLR4/MyD88 Pathway
复制标题
视黄醇结合蛋白 4 通过激活 TLR4/MyD88 通路诱导心肌细胞肥大
DOI：
10.1210/en.2015-2022
复制
发表时间：
2016-06-01
期刊：
影响因子：
4.8
通讯作者：
Lu, Xiang
中科院分区：
文献类型：
--
作者：
Gao, Wei;Wang, Hao;Lu, Xiang
胰岛素抵抗在心脏肥厚和心力衰竭的发生和发展中起着重要作用。心力衰竭反过来又会促进胰岛素抵抗，增加患糖尿病的风险。这种恶性循环决定了心力衰竭和糖尿病患者的显著死亡率。然而，恶性循环的潜在机制尚未完全阐明。本研究表明，在主动脉横缩和血管紧张素- ii （Ang-II）输注引起的心脏肥厚中，维生素a醇结合蛋白4 （RBP4）的循环水平和脂肪表达升高。RBP4是一种有助于全身胰岛素抵抗的脂肪因子。Ang-II增加了脂肪细胞中RBP4的表达，而这种表达被一种Ang-II受体阻滞剂氯沙坦所消除。心肌肥厚中RBP4的升高可能具有病理生理后果，因为RBP4增加了细胞大小，增强了蛋白质合成，并升高了原代心肌细胞中肥厚标志物（包括Anp、Bnp和Myh7）的表达。在机制上，RBP4诱导心肌细胞toll样受体4 （TLR4）和髓样分化初级反应基因88 （MyD88）的表达和活性，导致炎症和活性氧的产生增强。抑制或敲低TLR4/MyD88通路可减轻RBP4刺激引起的炎症和肥厚反应。重要的是，RBP4还降低了葡萄糖转运体-4的表达，并损害了胰岛素刺激的心肌细胞葡萄糖摄取。这种损伤在TLR4基因敲除小鼠的心肌细胞中得到改善。因此，RBP4可能是通过激活TLR4/ myd88介导的炎症通路促进胰岛素抵抗和心力衰竭恶性循环的关键调节剂。降低RBP4可能打破恶性循环，改善胰岛素抵抗和心脏肥厚。
Insulin resistance plays a major role in the development and progression of cardiac hypertrophy and heart failure. Heart failure in turn promotes insulin resistance and increases the risk for diabetes. The vicious cycle determines significant mortality in patients with heart failure and diabetes. However, the underlying mechanisms for the vicious cycle are not fully elucidated. Here we show that circulating levels and adipose expression of retinol-binding protein 4 (RBP4), an adipokine that contributes to systemic insulin resistance, were elevated in cardiac hypertrophy induced by transverse aortic constriction and angiotensin-II (Ang-II) infusion. Ang-II increased RBP4 expression in adipocytes, which was abolished by losartan, an Ang-II receptor blocker. The elevated RBP4 in cardiac hypertrophy may have pathophysiological consequences because RBP4 increased cell size, enhanced protein synthesis, and elevated the expression of hypertrophic markers including Anp, Bnp, and Myh7 in primary cardiomyocytes. Mechanistically, RBP4 induced the expression and activity of toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) in cardiomyocytes, resulting in enhanced inflammation and reactive oxygen species production. Inhibition or knockdown of the TLR4/MyD88 pathway attenuated inflammatory and hypertrophic responses to RBP4 stimulation. Importantly, RBP4 also reduced the expression of glucose transporter-4 and impaired insulin-stimulated glucose uptake in cardiomyocytes. This impairment was ameliorated in cardiomyocytes from TLR4 knockout mice. Therefore, RBP4 may be a critical modulator promoting the vicious cycle of insulin resistance and heart failure by activating TLR4/MyD88-mediated inflammatory pathways. Potentially, lowering RBP4 might break the vicious cycle and improve both insulin resistance and cardiac hypertrophy.