Disturbance of Fatty Acid Metabolism Promoted Vascular Endothelial Cell Senescence via Acetyl-CoA-Induced Protein Acetylation Modification.
Disturbance of Fatty Acid Metabolism Promoted Vascular Endothelial Cell Senescence via Acetyl-CoA-Induced Protein Acetylation Modification.
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脂肪酸代谢紊乱通过乙酰辅酶A诱导的蛋白质乙酰化修饰促进血管内皮细胞衰老
DOI：
10.1155/2022/1198607
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发表时间：
2022
影响因子：
--
通讯作者：
Li, Zhuo-ming
中科院分区：
文献类型：
--
作者：
Lin, Tong;Yang, Wan-qi;Luo, Wen-wei;Zhang, Li-li;Mai, Yan-qi;Li, Zi-qing;Liu, Si-tong;Jiang, Lu-jing;Liu, Pei-qing;Li, Zhuo-ming
内皮细胞衰老是导致血管功能障碍和与衰老相关的心血管疾病进展的主要危险因素。然而，内皮细胞代谢和内皮细胞衰老之间的关系仍不清楚。本研究为脂肪酸代谢在内皮细胞衰老调控中的作用提供了新的见解。在原代培养的人脐静脉内皮细胞（HUVECs）的复制性衰老模型和H2 O2诱导的早衰模型中，脂肪酸氧化（FAO）被抑制，脂肪酸谱被扰乱，伴随着与脂肪酸摄取和线粒体进入相关的蛋白质的下调，特别是FAO限速酶肉毒碱棕榈酰转移酶1A（CPT 1A）。通过沉默CPT 1A或CPT 1A抑制剂etomoxir来损害脂肪酸代谢促进内皮衰老的发展，如p53、p21和衰老相关β-半乳糖苷酶的增加以及EdU阳性增殖细胞的减少所暗示的。相反，通过过表达CPT 1A或补充短链脂肪酸（SCFAs）乙酸酯和丙酸酯来拯救FAO可改善内皮衰老。在体内，醋酸治疗4周降低血压，减轻衰老相关的表型在血管紧张素II输注小鼠的动脉瘤。从机制上讲，脂肪酸代谢通过乙酰辅酶A（乙酰辅酶A）调节内皮细胞衰老，这一点由以下观察结果所暗示：使用ATP柠檬酸裂解酶抑制剂NDI-091143抑制乙酰辅酶A的产生加速了HUVEC的衰老，并且补充乙酰辅酶A防止了H2 O2诱导的内皮细胞衰老。乙酰辅酶A的缺乏导致与细胞代谢和细胞周期相关的乙酰化蛋白质谱的改变。因此，这些发现表明脂肪酸代谢的改善可能会改善内皮衰老相关的心血管疾病。
Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated β-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.
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影响因子：
14.9
作者：
Kuosmanen SM;Kansanen E;Kaikkonen MU;Sihvola V;Pulkkinen K;Jyrkkänen HK;Tuoresmäki P;Hartikainen J;Hippeläinen M;Kokki H;Tavi P;Heikkinen S;Levonen AL
通讯作者：
Levonen AL
影响因子：
29
作者：
Lee JV;Carrer A;Shah S;Snyder NW;Wei S;Venneti S;Worth AJ;Yuan ZF;Lim HW;Liu S;Jackson E;Aiello NM;Haas NB;Rebbeck TR;Judkins A;Won KJ;Chodosh LA;Garcia BA;Stanger BZ;Feldman MD;Blair IA;Wellen KE
通讯作者：
Wellen KE
影响因子：
64.8
作者：
Hagberg, Carolina E.;Falkevall, Annelie;Eriksson, Ulf
通讯作者：
Eriksson, Ulf
影响因子：
37.8
作者：
Lewandowski, ED;Kudej, RK;Vatner, SF
通讯作者：
Vatner, SF
DOI：
10.3390/antiox10040572
发表时间：
2021-04-08
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Bradshaw PC
通讯作者：
Bradshaw PC