Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury.
Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury.
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DOI：
10.1371/journal.pone.0165576
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kaushal GP
中科院分区：
文献类型：
--
作者：
Bose C;Shah SV;Karaduta OK;Kaushal GP
慢性肾脏病（CKD）患者发生心血管并发症的风险较高。在CKD患者中，由尿素衍生的异氰酸酯或硫氰酸酯产生的氨甲酰化蛋白的血浆水平升高，并且它们是心血管事件和全因死亡率的重要预测因子。氨甲酰化低密度脂蛋白（cLDL）具有促动脉粥样硬化的特性，并已知影响与动脉粥样硬化相关的主要生物学过程，包括内皮细胞损伤。cLDL诱导的内皮细胞损伤的潜在机制尚未完全了解。虽然自噬与动脉粥样硬化有关，但cLDL介导的自噬诱导及其在内皮细胞损伤中的作用尚不清楚。我们的研究表明，人冠状动脉内皮细胞（HCAECs）通过特异性诱导关键自噬蛋白（包括LC 3-I，beclin-1，Atg 5），形成脂质结合的LC 3-II蛋白，以及形成自噬体相关LC 3-II的点状点来响应cLDL。我们证明了自噬诱导是对cLDL的立即反应，并且以剂量和时间依赖性方式发生。通过针对LC 3的特异性siRNA以及通过自噬抑制剂抑制cLDL诱导的自噬提供了针对cLDL诱导的细胞死亡和DNA片段化的保护。我们的研究表明，自噬在cLDL介导的内皮细胞损伤中起重要作用，并可能为CKD患者cLDL诱导的动脉粥样硬化的发病机制之一。
Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL-mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients.
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影响因子：
3.7
作者：
Chandrika BB;Yang C;Ou Y;Feng X;Muhoza D;Holmes AF;Theus S;Deshmukh S;Haun RS;Kaushal GP
通讯作者：
Kaushal GP
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16
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影响因子：
64.5
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Levine B
影响因子：
20.1
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通讯作者：
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影响因子：
20.1
作者：
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通讯作者：
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