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Review
. 2013 Feb 15;304(4):H491-500.
doi: 10.1152/ajpheart.00721.2012. Epub 2012 Dec 15.

Impact of glucose-6-phosphate dehydrogenase deficiency on the pathophysiology of cardiovascular disease

Peter A Hecker  1 , Jane A Leopold, Sachin A Gupte, Fabio A Recchia, William C Stanley
Affiliations
Review

Impact of glucose-6-phosphate dehydrogenase deficiency on the pathophysiology of cardiovascular disease

Peter A Hecker et al. Am J Physiol Heart Circ Physiol. .

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the rate-determining step in the pentose phosphate pathway and produces NADPH to fuel glutathione recycling. G6PD deficiency is the most common enzyme deficiency in humans and affects over 400 million people worldwide; however, its impact on cardiovascular disease is poorly understood. The glutathione pathway is paramount to antioxidant defense, and G6PD-deficient cells do not cope well with oxidative damage. Limited clinical evidence indicates that G6PD deficiency may be associated with hypertension. However, there are also data to support a protective role of G6PD deficiency in decreasing the risk of heart disease and cardiovascular-associated deaths, perhaps through a decrease in cholesterol synthesis. Studies in G6PD-deficient (G6PDX) mice are mixed and provide evidence for both protective and deleterious effects. G6PD deficiency may provide a protective effect through decreasing cholesterol synthesis, superoxide production, and reductive stress. However, recent studies indicate that G6PDX mice are moderately more susceptible to ventricular dilation in response to myocardial infarction or pressure overload-induced heart failure. Furthermore, G6PDX hearts do not recover as well as nondeficient mice when faced with ischemia-reperfusion injury, and G6PDX mice are susceptible to the development of age-associated cardiac hypertrophy. Overall, the limited available data indicate a complex interplay in which adverse effects of G6PD deficiency may outweigh potential protective effects in the face of cardiac stress. Definitive clinical studies in large populations are needed to determine the effects of G6PD deficiency on the development of cardiovascular disease and subsequent outcomes.

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Figures

Fig. 1.
Fig. 1.
The pentose phosphate pathway. The oxidative phase of the pentose phosphate pathway produces NADPH from NADP+ and ribulose-5-phosphate. Ribulose-5-phosphate may be converted to glyceraldehydes-3-phosphate and fructose-6-phosphate through a series of nonoxidative reactions. 6PGD, 6-phosphogluconate dehydrogenase; G6PD, glucose-6-phosphate dehydrogenase.
Fig. 2.
Fig. 2.
Role of G6PD in both antioxidant and oxidant formation pathways. The pentose phosphate pathway produces NADPH through G6PD and 6PGD. NADPH supports the antioxidant glutathione pathway in which glutathione reductase (GR) uses NADPH to reduce oxidized glutathione (GSSG) to reduced glutathione (GSH) for use by glutathione peroxidase (GPx) to reduce H2O2 to H2O. On the other hand, NADPH is also used to produce superoxide (O2·−) via NADPH oxidase, uncoupled nitric oxide synthase, and xanthine oxidase. O2·− is converted to H2O2 by O2·− dismutase (SOD), and the overproduction of these reactive oxygen species may adversely affect cell function.
Fig. 3.
Fig. 3.
G6PD expression in various human tissues. Graphical microarray mRNA expression data were obtained from biogps.org using the GeneAtlas U133A, gcrma data set from Su et al. (102a).
Fig. 4.
Fig. 4.
G6PD inhibition decreases NADPH levels and O2·− production in failing myocardium. Myocardium was obtained from failing and nonfailing patients undergoing cardiac surgery. NADPH levels and O2·− production were assessed in myocardial homogenates in the presence or absence of the G6PD inhibitor 6-aminonicotinamide. *P < 0.05 vs. normal; #P < 0.04 vs. heart failure. Reprinted with permission from Gupte et al. (32) with modifications.
Fig. 5.
Fig. 5.
G6PD deficiency adversely affects the outcome of ischemia-reperfusion injury. G6PD-deficient (G6PDX) mouse hearts have a decreased capacity to recover from acute ischemia-reperfusion injury. Isolated mouse hearts were perfused retrograde using Langendorff system, where isovolumic left ventricular (LV) pressure was measured at baseline and with 15 min of no-flow global ischemia followed by 30 min of reperfusion. WT, wild-type. *P < 0.05 vs. WT. Reprinted with permission from Jain et al. (45).
Fig. 6.
Fig. 6.
Adverse effects of G6PD deficiency on heart failure. Sixteen week-old male mice underwent sham surgery or permanent coronary occlusion to induce myocardial infarction. Cardiac function was assessed at 11 wk by echocardiography. G6PDX mice developed greater LV chamber expansion (A) and dilation (B) in response to myocardial infarction. *P < 0.05 vs. respective sham; #P < 0.05 vs. WT infarct. Reprinted from Hecker et al. (39).
Fig. 7.
Fig. 7.
Effects of changes in NADPH levels. Increasing NADPH fuels superoxide production by NADPH oxidase or may contribute to reductive stress. Decreasing NADPH may limit cholesterol synthesis but also decreases antioxidant capacity.
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