Figure 2.

Pressure-overload activates both NOX2 and NOX4 in the heart. NOX2 down-regulates the transcription factor PPARα and PGC1α. This may have subsequent downstream effects on metabolic gene programmes including glucose oxidation and FAO and potential for lipotoxicity. NOX4 augments FAO in cardiomyocytes via an ATF4-dependent mechanism leading to preserved myocardial energetics. Increasing flux through a branch pathway of glycolysis, the HBP, via up-regulation of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) expression leads to the formation of UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is used by O-GlcNAc transferase (Ogt) to post-translationally modify specific serine and threonine residues of proteins by O-linked-N-acetylglucosaminylation (O-GlcNAcylation). Such O-GlcNAc modification of Cd36/fatty acid translocase results in an increased uptake and metabolism of fatty acids. It should be noted that broad suppression of NOX-derived ROS causes an up-regulation of PPARα leading to lipotoxicity in the setting of ischaemia–reperfusion injury.