Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells.
Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells.
复制标题
DOI：
10.1016/j.jss.2017.02.028
复制
发表时间：
2017-06-01
期刊：
影响因子：
--
通讯作者：
Meng X
中科院分区：
文献类型：
--
作者：
Cheng H;Yao Q;Song R;Zhai Y;Wang W;Fullerton DA;Meng X
主动脉瓣间质细胞 (AVIC) 过度产生细胞外基质 (ECM) 蛋白，在与主动脉瓣狭窄早期病理学相关的瓣膜硬化（增厚）中发挥着重要作用。在硬化主动脉瓣中观察到氧化低密度脂蛋白（oxLDL）的积累，并且可能在瓣膜疾病进展中具有机制作用。溶血磷脂酰胆碱 (LysoPC) 是 oxLDL 的组成部分，具有多种生物活性。本研究旨在检验 oxLDL 和 LysoPC 上调人类 AVIC 中 ECM 蛋白产生的假设。 AVIC 是从正常人主动脉瓣中分离出来的。用oxLDL (40 μg/ml) 或LysoPC (40 μmol/L) 处理细胞。应用免疫印迹法分析细胞裂解物中的 ECM 蛋白（胶原蛋白 I、III 和双糖链蛋白聚糖），并使用天狼星红染色检查胶原蛋白沉积。 oxLDL 和 LysoPC 均上调双糖链蛋白聚糖和 I 型胶原蛋白的产生。LysoPC 对 ECM 蛋白的上调先于 Akt 和 ERK1/2 的磷酸化。抑制 Akt 显着降低 LysoPC 对 ECM 蛋白产生和胶原蛋白沉积的影响。然而，抑制 ERK1/2 没有效果。 LysoPC 上调人 AVIC 中双糖链蛋白聚糖和 I 型胶原蛋白的产生，并可能介导 oxLDL 对 ECM 蛋白产生的影响。 Akt 通路似乎对于介导 LysoPC 的作用至关重要。主动脉瓣组织中 OxLDL 的积累和 LysoPC 的产生可能有助于与主动脉瓣狭窄发生和进展相关的瓣膜硬化机制。
Overproduction of extracellular matrix (ECM) protein by aortic valve interstitial cells (AVICs) plays an important role in valvular sclerosis (thickening) associated with the early pathobiology of aortic stenosis. Accumulation of oxidized low-density lipoprotein (oxLDL) is observed in sclerotic aortic valve and may have a mechanistic role in valvular disease progression. Lysophosphatidylcholine (LysoPC) is a component of oxLDL and has multiple biological activities. This study was to test the hypothesis that oxLDL and LysoPC up-regulate ECM protein production in human AVICs. AVICs were isolated from normal human aortic valves. Cells were treated with oxLDL (40 μg/ml) or LysoPC (40 μmol/L). Immunoblotting was applied to analyze ECM proteins (collagens I, III and biglycan) in cell lysate and Picrosirius red staining is used to examine collagen deposition. Both oxLDL and LysoPC up-regulated the production of biglycan and collagen I. The up-regulation of ECM proteins by LysoPC was preceded by the phosphorylation of Akt and ERK1/2. Inhibition of Akt markedly reduced the effect of LysoPC on ECM protein production and collagen deposition. However, inhibition of ERK1/2 had no effect. LysoPC up-regulates the production of biglycan and collagen I in human AVICs and may mediate the effect of oxLDL on ECM protein production. The Akt pathway appears to be critical in mediating the effect of LysoPC. OxLDL accumulation and generation of LysoPC in the aortic valve tissue may contribute to the mechanism of valvular sclerosis associated with the development and progression of aortic stenosis.