α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt.
α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt.
复制标题
DOI：
10.1016/j.ebiom.2021.103672
复制
发表时间：
2021-11
期刊：
影响因子：
11.1
通讯作者：
Guchhait P
中科院分区：
文献类型：
--
作者：
Shrimali NM;Agarwal S;Kaur S;Bhattacharya S;Bhattacharyya S;Prchal JT;Guchhait P
磷酸-Akt 1（pAkt 1）在α-酮戊二酸（αKG）脱羧反应中通过脯氨酰羟化酶-2（PHD 2）在Pro 125和Pro 313处发生脯氨酰羟化。我们研究了补充αKG是否可以通过增强PHD 2活性来抑制Akt介导的血小板和单核细胞活化，无论是在体外还是体内。我们在体外用αKG在存在激动剂的情况下处理从健康个体分离的血小板或单核细胞，并评估包括pAkt 1在内的信号分子。我们用膳食αKG补充小鼠，并估计离体血小板和单核细胞的功能反应。此外，我们研究了饮食αKG对用血栓诱导剂角叉菜胶处理或感染SARS-CoV-2的小鼠肺部炎症和血栓形成的影响。向血小板补充辛基αKG通过升高细胞内αKG与琥珀酸酯的比例促进PHD 2活性，并通过抑制pAkt 1（Thr 308）减少体外聚集。在α KG处理的血小板中，增加的羟化脯氨酸和增强的PHD 2与pAkt的结合证实了PHD 2活性增强。相反，PHD 2抑制剂显著增加血小板中的pAkt 1。Octyl-αKG在单核细胞中遵循类似的机制来抑制体外细胞因子分泌。我们的数据还描述了补充膳食αKG的小鼠的pAkt 1抑制和血小板和白细胞离体活化减少，但未伴随其数量的改变。膳食αKG显著减少了血栓形成诱导剂角叉菜胶处理的小鼠包括肺在内的各种器官中的凝块形成和白细胞积聚。重要的是，在SARS-CoV-2感染的仓鼠中，我们观察到饮食αKG对发炎的肺具有显著的拯救作用，显著减少白细胞积聚、凝块形成和病毒载量，同时下调感染动物肺中的pAkt。我们的研究表明，膳食αKG补充剂可预防Akt驱动的疾病，如血栓形成和炎症，并挽救COVID 19感染肺部的病理。本研究由印度政府生物技术部（DBT）（赠款：BT/PR 22881和BT/PR 22985）和印度政府科学与工程研究委员会（CRG/000092）资助。
Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).
登录
查看更多内容
影响因子：
--
作者：
He L;Li H;Huang N;Zhou X;Tian J;Li T;Wu J;Tian Y;Yin Y;Yao K
通讯作者：
Yao K
影响因子：
9.3
作者：
Hagimori, Masayori;Kamiya, Seitaro;Arakawa, Masayuki
通讯作者：
Arakawa, Masayuki
影响因子：
64.5
作者：
Bouhaddou, Mehdi;Memon, Danish;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
影响因子：
10.4
作者：
Hogberg, C.;Gidlof, O.;Olde, B.
通讯作者：
Olde, B.
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny