Oxidized Phosphatidylcholines Activate NOX1-Mediated Oxidative Stress Response and Shift Glucose Metabolism in Cardiac Cells.

In cardiometabolic syndrome the development of cardiovascular disease is linked with an increase in systemic oxidative stress. The formation of free radical species leads to the oxidative modification of lipids, including phosphatidylcholines (OxPCs), which have been implicated in the progression of cardiovascular diseases in humans. We found that reducing plasma levels of OxPCs in mice by AAV-mediated hepatic expression of an OxPC-targeting antibody fragment (scFv-E06), resulted in significant transcriptional changes in the heart, particularly affecting genes involved in metabolism, redox processes, and fibrosis. To investigate the response of cardiac myoblasts to OxPCs in vitro, we exposed H9c2 cells to a defined mixture of OxPC species (OxPAPC). Treatment with OxPAPC resulted in transcriptional upregulation of key metabolic and redox-regulatory pathways, most notably genes regulated by the Nrf2 pathway, including heme oxygenase 1 (Hmox1). OxPAPC induced reactive oxygen species (ROS) production in H9c2 cells through activation NADPH oxidase 1 (Nox1), which upregulated the production of oxidized glutathione. Key metabolic changes after exposure to OxPAPC included a shift towards the pentose phosphate pathway (PPP) and suppression of glycolysis, resulting in overall decreased ATP production. Furthermore, OxPAPC downregulated oxidative phosphorylation in H9c2 cells through a mechanism involving activation of the MEK-ERK mitogen-activated protein kinase (MAPK) pathway. Together, these data demonstrate that cardiac myoblasts respond to OxPCs by upregulating redox regulatory pathways and shifts in cellular energy production. Furthermore, we identify NOX1 as a novel mediator of OxPC-induced redox stress that may induce cardiac cell damage in cardiometabolic syndrome.