| First Author | Shrimali NM | Year | 2021 |
| Journal | EBioMedicine | Volume | 73 |
| Pages | 103672 | PubMed ID | 34740102 |
| Mgi Jnum | J:351438 | Mgi Id | MGI:6825948 |
| Doi | 10.1016/j.ebiom.2021.103672 | Citation | Shrimali NM, et al. (2021) alpha-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt. EBioMedicine 73:103672 |
| abstractText | BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating alpha-ketoglutarate (alphaKG). We investigated whether the alphaKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with alphaKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary alphaKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary alphaKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl alphaKG supplementation to platelets promoted PHD2 activity through elevated intracellular alphaKG 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 alphaKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-alphaKG 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 alphaKG, unaccompanied by alteration in their number. Dietary alphaKG 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 alphaKG 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. INTERPRETATION: Our study suggests that dietary alphaKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: 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). |
