α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway.
α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway.
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DOI：
10.1111/j.1582-4934.2011.01294.x
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发表时间：
2012-02
影响因子：
5.3
通讯作者：
Lee IK
中科院分区：
文献类型：
--
作者：
Kim H;Kim HJ;Lee K;Kim JM;Kim HS;Kim JR;Ha CM;Choi YK;Lee SJ;Kim JY;Harris RA;Jeong D;Lee IK
血管钙化在慢性肾病患者中普遍存在，并导致心血管发病率和死亡率增加。虽然有几个报告涉及心血管疾病和慢性肾脏疾病的线粒体功能障碍，很少有人知道的血管钙化过程中的线粒体功能障碍的潜在作用。本研究探讨了α-硫辛酸（ALA），一种天然存在的抗氧化剂，改善线粒体功能，在体外和体内对血管钙化的影响。无机磷酸盐（Pi）处理的钙化血管平滑肌细胞（VSMCs）表现出线粒体功能障碍，表现为线粒体膜电位和ATP生成降低，线粒体结构完整性破坏，同时活性氧生成增加。这些Pi诱导的线粒体功能和结构缺陷伴随着线粒体依赖性凋亡事件，包括细胞色素c从线粒体释放到胞质溶胶中，随后激活caspase-9和-3，以及染色体DNA片段化。有趣的是，ALA通过恢复线粒体功能和细胞内氧化还原状态来阻断Pi诱导的VSMC凋亡和钙化。此外，ALA通过生长抑制特异性基因6（Gas 6）与其同源受体Axl的结合和随后的Akt激活来抑制Pi诱导的细胞存活信号的下调，从而导致存活增加和凋亡减少。最后，ALA显着改善维生素D3诱导的小鼠主动脉钙化和线粒体损伤。总的来说，研究结果表明ALA通过两种不同的机制抑制VSMC凋亡来减弱血管钙化;通过其抗氧化潜力和Gas 6/Axl/Akt存活途径恢复线粒体功能。
Vascular calcification is prevalent in patients with chronic kidney disease and leads to increased cardiovascular morbidity and mortality. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. This study investigated the effect of α-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity and concurrently increased production of reactive oxygen species. These Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. Intriguingly, ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced down-regulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. Finally, ALA significantly ameliorated vitamin D3-induced aortic calcification and mitochondrial damage in mice. Collectively, the findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; preservation of mitochondrial function via its antioxidant potential and restoration of the Gas6/Axl/Akt survival pathway.
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影响因子：
20.1
作者：
Li, XW;Yang, HY;Giachelli, CM
通讯作者：
Giachelli, CM
影响因子：
4.8
作者：
Byon, Chang Hyun;Javed, Amjad;Chen, Yabing
通讯作者：
Chen, Yabing
DOI：
10.1196/annals.1395.024
发表时间：
2007-01-01
期刊：
BIOGERONTOLOGY: MECHANISMS AND INTERVENTIONS
影响因子：
--
作者：
Krishnan, Kim J.;Greaves, Laura C.;Turnbull, Douglass M.
通讯作者：
Turnbull, Douglass M.
影响因子：
13.6
作者：
Kestenbaum, B;Sampson, JN;Andress, DL
通讯作者：
Andress, DL
影响因子：
3.9
作者：
Bindoli, A;Callegaro, MT;Rigobello, MP
通讯作者：
Rigobello, MP