Masoud, AG;
Lin, J;
Zhu, LF;
Tao, K;
Ness, NW;
Kassiri, Z;
Moore, RB;
... Murray, AG; + view all
(2023)
Endothelial phosphoinositide 3-kinase-β inactivation confers protection from immune-mediated vascular injury.
American Journal of Transplantation
, 23
(2)
pp. 202-213.
10.1016/j.ajt.2022.11.014.
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Abstract
Heart transplant and recipient survival are limited by immune cell-mediated injury of the graft vasculature. We examined the role of the phosphoinositide 3-kinase-β (PI3Kβ) isoform in endothelial cells (EC) during coronary vascular immune injury and repair in mice. In minor histocompatibility-antigen mismatched allogeneic heart grafts, a robust immune response was mounted to each wild-type, PI3Kβ inhibitor-treated, or endothelial-selective PI3Kβ knockout (ECβKO) graft transplanted to wild-type recipients. However, microvascular EC loss and progressive occlusive vasculopathy only developed in control, but not PI3Kβ-inactivated hearts. We observed a delay in inflammatory cell infiltration of the ECβKO grafts, particularly in the coronary arteries. Surprisingly, this was accompanied by an impaired display of proinflammatory chemokine and adhesion molecules by the ECβKO ECs. In vitro, tumor necrosis factor α-stimulated endothelial ICAM1 and VCAM1 expression was blocked by PI3Kβ inhibition or RNA interference. Selective PI3Kβ inhibition also blocked tumor necrosis factor α-stimulated degradation of inhibitor of nuclear factor kappa Bα and nuclear translocation of nuclear factor kappa B p65 in EC. These data identify PI3Kβ as a therapeutic target to reduce vascular inflammation and injury.
| Type: | Article |
|---|---|
| Title: | Endothelial phosphoinositide 3-kinase-β inactivation confers protection from immune-mediated vascular injury |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ajt.2022.11.014 |
| Publisher version: | https://doi.org/10.1016/j.ajt.2022.11.014 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | animal models: murine, basic (laboratory) research/science, cellular biology, heart transplantation/cardiology, immunosuppressive regimens–rescue, rejection: chronic, rejection: vascular, signaling/signaling pathways: PI-3 kinase/AKT pathway, translational research/science, Mice, Animals, Endothelial Cells, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Vascular System Injuries, Tumor Necrosis Factor-alpha |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166637 |
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