Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling.
Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling.
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Hemeoxygenase-1 通过调节内皮一氧化氮合酶的激活和偶联来改善氧化应激诱导的内皮衰老。
DOI：
10.18632/aging.101506
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发表时间：
2018-07-24
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Luo W;Wang Y;Yang H;Dai C;Hong H;Li J;Liu Z;Guo Z;Chen X;He P;Li Z;Li F;Jiang J;Liu P;Li Z
目的：血管内皮细胞过早衰老是导致多种心血管疾病的主要原因。针对内皮细胞衰老的治疗具有重要的临床意义。本研究旨在评估血红素加氧酶-1 （HO-1）作为内皮细胞衰老治疗靶点的潜力。方法与结果：Hemin或腺病毒感染上调HO-1可逆转h2o2诱导的人脐静脉内皮细胞（HUVECs）衰老；而通过siRNA或HO-1抑制剂原卟啉IX锌（II） （ZnPP）耗尽HO-1会引发HUVEC衰老。从机制上讲，HO-1的过表达增强了HO-1与内皮型一氧化氮合酶（eNOS）的相互作用，并促进了eNOS与其上游激酶Akt的相互作用，从而导致eNOS Ser1177位点磷酸化增强，进而增加一氧化氮（NO）的产生。此外，HO-1诱导可通过其抗氧化性阻止H2O2诱导的eNOS二聚体/单体比降低。相反，HO-1沉默会破坏eNOS磷酸化并加速eNOS解偶联。在体内，Hemin通过上调eNOS Ser1177位点的磷酸化，减轻了自发性高血压大鼠主动脉内皮细胞的衰老。结论：HO-1通过增强eNOS激活和保护eNOS解偶联来改善内皮细胞衰老，提示HO-1是治疗内皮细胞衰老的潜在靶点。
Aim: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence. Methods and Results: Upregulation of HO-1 by Hemin or adenovirus infection reversed H2O2-induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by H2O2 via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. In vivo, Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177. Conclusions: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.
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影响因子：
2.9
作者：
FRYDMAN, RB;TOMARO, ML;FRYDMAN, B
通讯作者：
FRYDMAN, B
影响因子：
37.8
作者：
Förstermann, U;Münzel, T
通讯作者：
Münzel, T
影响因子：
5
作者：
Donato AJ;Morgan RG;Walker AE;Lesniewski LA
通讯作者：
Lesniewski LA
影响因子：
4.8
作者：
Alam, J;Stewart, D;Cook, JL
通讯作者：
Cook, JL
影响因子：
5.3
作者：
Brown, Melanie F.;Stuart, Jeffrey A.
通讯作者：
Stuart, Jeffrey A.