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Review
. 2023 Jan 18;118(17):3305-3319.
doi: 10.1093/cvr/cvac030.

The regulation of cardiac intermediary metabolism by NADPH oxidases

Adam A Nabeebaccus  1 , Christina M Reumiller  1 , Jie Shen  1 , Anna Zoccarato  1 , Celio X C Santos  1 , Ajay M Shah  1
Affiliations
Review

The regulation of cardiac intermediary metabolism by NADPH oxidases

Adam A Nabeebaccus et al. Cardiovasc Res. .

Abstract

NADPH oxidases (NOXs), enzymes whose primary function is to generate reactive oxygen species, are important regulators of the heart's physiological function and response to pathological insults. The role of NOX-driven redox signalling in pathophysiological myocardial remodelling, including processes such as interstitial fibrosis, contractile dysfunction, cellular hypertrophy, and cell survival, is well recognized. While the NOX2 isoform promotes many detrimental effects, the NOX4 isoform has attracted considerable attention as a driver of adaptive stress responses both during pathology and under physiological states such as exercise. Recent studies have begun to define some of the NOX4-modulated mechanisms that may underlie these adaptive responses. In particular, novel functions of NOX4 in driving cellular metabolic changes have emerged. Alterations in cellular metabolism are a recognized hallmark of the heart's response to physiological and pathological stresses. In this review, we highlight the emerging roles of NOX enzymes as important modulators of cellular intermediary metabolism in the heart, linking stress responses not only to myocardial energetics but also other functions. The novel interplay of NOX-modulated redox signalling pathways and intermediary metabolism in the heart is unravelling a new aspect of the fascinating biology of these enzymes which will inform a better understanding of how they drive adaptive responses. We also discuss the implications of these new findings for therapeutic approaches that target metabolism in cardiac disease.

Keywords: Cardiac metabolism; Intermediary metabolism; NADPH oxidases; Redox signalling.

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Conflict of interest statement

Conflict of interest: A.M.S. serves as an adviser to Forcefield Therapeutics and CYTE—Global Network for Clinical Research. This manuscript was handled by Reviews Deputy Editor Dr Ali J. Marian. None of the other authors declare any conflict of interest.

Figures

Figure 1
Figure 1
NOX2 and NOX4 are the major isoforms present in the cardiomyocyte. They are activated by a variety of stimuli (e.g. cytokines, mechanical stretch, growth factors, nutrient deprivation, metabolites) and G-protein coupled receptor agonists such as angiotensin II (Ang II) and endothelin-1 (ET-1). Their intracellular locations are also distinct, with NOX2 being located at the sarcolemma and NOX4 located in intracellular membrane compartments (ER/mitochondria/MAM). Another distinction between isoforms is the ROS produced. NOX2 generates superoxide (O2.-) but NOX4 generates predominantly hydrogen peroxide (H2O2). It is likely that the differing intracellular locations and ROS-generating properties underlie their functional differences. PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; EGF, epidermal growth factor; oxLDL, oxidized LDL.
Figure 2
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.
Figure 3
Figure 3
ER stressors activate/induce both NOX2 and NOX4 but lead to different effects on cell fate. ER stress activates the UPR through the interaction of molecular chaperones like BiP with specific pathways that can lead to either cell death or cell survival. NOX2 induces ER stress leading to apoptosis in response to a variety of ER-stress stimuli including diabetes, ischaemia, and adrenergic agonist stimulation. NOX2 can increase levels of CHOP which signals to activation of cell death pathways and adverse cardiac remodelling. NOX2 can also induce ATF6 at least in chronic hyperglycaemic conditions. During ischaemia–reperfusion, ER-located NOX4 can specifically activate the ISR leading to the activation of cell survival pathways. Specifically, NOX4 mediates oxidation of the PP1 metal centre to inactivate the enzyme and sustain eIF2α phosphorylation and ATF4 activation (eIF2α-ATF4 limb). This is independent of the other arms of the UPR, namely the IRE1α-XBP1 pathway (shown for illustration) or the ATF6 pathway. ERAD, ER-associated protein degradation; GADD34, growth arrest and DNA damage-inducible 34; BiP, binding immunoglobulin protein.
Figure 4
Figure 4
The MAM represents a unique compartment enabling NOX4-localized ROS signalling and ER-mitochondrial calcium communication. Serum starvation or ischaemia–reperfusion (IR) injury can lead to mitochondrial calcium overload and cell death but an increase in NOX4 levels at the MAM prevents excessive calcium transfer between the ER and mitochondria, thereby inhibiting opening of the mitochondrial permeability transition pore and cell death. Mechanistically, NOX4 results in the enhancement of MAM-located Akt activity via a redox inhibition of the phosphatase PP2a. Akt in turn is able to phosphorylate ER InsP3R channels which decrease the release of calcium from the ER to the mitochondria.
Figure 5
Figure 5
Both NOX2 and NOX4, the main NOX isoforms in cardiomyocytes, can regulate intermediary metabolism in response to a variety of stresses. Several mechanisms are involved, including activation of transcription factors or in the case of NOX4 location at the MAM, targeted ROS signalling to influence mitochondrial function and cell viability. ATF4, activating transcription factor 4; NRF2, nuclear factor erythroid factor 2-related factor 2; HIF1α, hypoxia-inducible factor 1-alpha; ISR, integrated stress response.
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