Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression
Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression
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蛋白激酶 C 通过调节半乳糖凝集素 3 的表达促进心脏纤维化和心力衰竭。
DOI：
10.1016/j.bbamcr.2014.12.001
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发表时间：
2015-02-01
影响因子：
5.1
通讯作者：
Shen, Baozhong
中科院分区：
文献类型：
--
作者：
Song, Xiang;Qian, Xiaoqian;Shen, Baozhong
蛋白激酶C（PKC）和半乳糖凝集素-3（Galectin-3）是两种重要的介质，在心肌肥厚和心力衰竭（HF）中发挥关键的致病作用。然而，其分子机制和信号通路尚未完全了解。在这项研究中，我们探讨了PKC-α和galectin-3在HF发生发展中的关系和作用。我们发现在培养的HL-1心肌细胞中，佛波醇二丁酸酯（PDB）激活PKC使半乳糖凝集素-3的表达增加了180%，同时胶原和纤维连接蛋白的积累也增加了。Galectin-3在HL-1细胞中的过表达增加了I型胶原蛋白的产生。β-乳糖对半乳糖凝集素-3的抑制阻断了PDB诱导的半乳糖凝集素-3和胶原蛋白的产生，表明半乳糖凝集素-3介导PKC诱导的心脏纤维化。在进行肺动脉结扎（PAB）以诱导右心室HF的大鼠中，与对照相比，半乳糖凝集素-3在右心室中增加了类似于140%，在左心室中也增加了类似于240%。半乳糖凝集素-3升高与总PKC-α和活化（磷酸化）PKC-α、α-SMA和胶原蛋白I增加一致。最后，我们扩展了我们的研究结果，以检查血管紧张素II（Ang II）的作用，它激活PKC通路，并有助于心脏纤维化和HF的发展。我们发现，血管紧张素II激活PKC-α途径，增加半乳糖凝集素-3的表达和胶原蛋白的生产。本研究为探讨PKC-α和galectin-3介导的HF的分子机制提供了新的思路。PKC-α通过刺激半乳糖凝集素-3表达促进心脏纤维化和HF。（C）2014 Elsevier B.V.保留所有权利。
Protein kinase C (PKC) and galectin-3 are two important mediators that play a key pathogenic role in cardiac hypertrophy and heart failure (HF). However, the molecular mechanisms and signaling pathways are not fully understood. In this study, we explored the relationship between and roles of PKC-alpha and galectin-3 in the development of HF. We found that activation of PKC by phorbol dibutyrate (PDB) increased galectin-3 expression by similar to 180%, as well as collagen land fibronection accumulation in cultured HL-1 cardiomyocytes. Over-expression of galectin-3 in HL-1 cells increased collagen I protein production. Inhibition of galectin-3 by beta-lactose blocked PDB-induced galectin-3 and collagen production, indicating that galectin-3 mediates PKC-induced cardiac fibrosis. In rats subjected to pulmonary artery banding (PAB) to induce right ventricular HF, galectin-3 was increased by similar to 140% in the right ventricle and also by similar to 240% in left ventricle compared to control. The elevated galectin-3 is consistent with an increase of total and activated (phosphorylated) PKC-alpha, alpha-SMA and collagen I. Finally, we extended our findings to examine the role of angiotensin II (Ang II), which activates the PKC pathway and contributes to cardiac fibrosis and the development of HF. We found that Ang II activated the PKC-alpha pathway and increased galectin-3 expression and collagen production. This study provides a new insight into the molecular mechanisms of HF mediated by PKC-alpha and galectin-3. PKC-alpha promotes cardiac fibrosis and HF by stimulation of galectin-3 expression. (C)2014 Elsevier B.V. All rights reserved.