A cell permeant phosphopeptide mimetic of Niban inhibits p38 MAPK and restores endothelial function after injury.

Tsz Wing Yim, Daniel Perling, Monica Polcz, Padmini Komalavilas, Colleen Brophy, Joyce Cheung-Flynn

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Jul

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Vascular injury leads to membrane disruption, ATP release, and endothelial dysfunction. Increases in the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and decreases in the phosphorylation of Niban, a protein implicated in ER stress and apoptosis, are associated with vascular injury. A cell permeant phosphopeptide mimetic of Niban (NiPp) was generated. The effects of NiPp in restoring endothelial function were determined ex vivo using intact rat aortic tissue (RA) after pharmacological activation of p38 MAPK and also in multiple clinically relevant injury models. Anisomycin (Aniso) increased p38 MAPK phosphorylation and reduced endothelial-dependent relaxation in RA. Treatment with NiPp prevented Ansio-induced reduction in endothelial function and increases in p38 MAPK phosphorylation. NiPp treatment also restored endothelial function after stretch injury (subfailure stretch), treatment with acidic Normal Saline (NS), and P2X7R activation with 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate (BzATP). Aged, diseased, human saphenous vein (HSV) remnants obtained from patients undergoing coronary bypass surgical procedures have impaired endothelial function. Treatment of these HSV segments with NiPp improved endothelial-dependent relaxation. Kinome screening experiments indicated that NiPp inhibits p38 MAPK. These data demonstrate that p38 MAPK and Niban signaling have a role in endothelial function, particularly in response to injury. Niban may represent an endogenous regulator of p38 MAPK activation. The NiPp peptide may serve as an experimental tool to further elucidate p38 MAPK regulation and as a potential therapeutic for endothelial dysfunction. © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Citation

Tsz Wing Yim, Daniel Perling, Monica Polcz, Padmini Komalavilas, Colleen Brophy, Joyce Cheung-Flynn. A cell permeant phosphopeptide mimetic of Niban inhibits p38 MAPK and restores endothelial function after injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Jul;34(7):9180-9191