Nitric Oxide Maintains Endothelial Redox Homeostasis Through PKM2 Inhibition

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2019 Jul 23

PMID 31328803

Citations 26

Authors

Mauro Siragusa

Janina Thole

Sofia-Iris Bibli

Bert Luck

Annemarieke E Loot

Kevin De Silva

Ilka Wittig

Juliana Heidler

Heike Stingl

Voahanginirina Randriamboavonjy

Karin Kohlstedt

Bernhard Brune

Andreas Weigert

Beate Fisslthaler

Ingrid Fleming

Affiliations

Soon will be listed here.

Abstract

Decreased nitric oxide (NO) bioavailability and oxidative stress are hallmarks of endothelial dysfunction and cardiovascular diseases. Although numerous proteins are S-nitrosated, whether and how changes in protein S-nitrosation influence endothelial function under pathophysiological conditions remains unknown. We report that active endothelial NO synthase (eNOS) interacts with and S-nitrosates pyruvate kinase M2 (PKM2), which reduces PKM2 activity. PKM2 inhibition increases substrate flux through the pentose phosphate pathway to generate reducing equivalents (NADPH and GSH) and protect against oxidative stress. In mice, the Tyr656 to Phe mutation renders eNOS insensitive to inactivation by oxidative stress and prevents the decrease in PKM2 S-nitrosation and reducing equivalents, thereby delaying cardiovascular disease development. These findings highlight a novel mechanism linking NO bioavailability to antioxidant responses in endothelial cells through S-nitrosation and inhibition of PKM2.

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