Regulation of and intervention into the oxidative pentose phosphate pathway and adenine nucleotide metabolism in the heart

Abstract

The capacity of the oxidative pentose pathway (PPP) in the heart is limited, since the activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of this pathway, is very low. Two mechanisms are involved in the regulation of this pathway. Under normal conditions, G-6-PD is inhibited by NADPH. This can be overcome in the isolated perfused rat heart by increasing the oxidized glutathione and by elevating the NADP+/NADPH ratio. Besides this rapid control mechanism, there is a long-term regulation which involves the synthesis of G-6-PD. The activity of G-6-PD was elevated in the rat heart during the development of cardiac hypertrophy due to constriction of the abdominal aorta and in the non-ischemic part of the rat heart subsequent to myocardial infarction. The catecholamines isoproterenol and norepinephrine stimulated the activity of myocardial G-6-PD in a time- and dose-dependent manner. The isoproterenol-induced stimulation was cAMP-dependent and due to increased new synthesis of enzyme protein. The G-6-PD mRNA was elevated by norepinephrine. As a consequence of the stimulation of the oxidative PPP, the available pool of 5-phosphoribosyl-1-pyrophosphate (PRPP) was expanded. PRPP is an important precursor substrate for purine and pyrimidine nucleotide synthesis. The limiting step in the oxidative PPP, the G-6-PD reaction, can be bypassed with ribose. This leads to an elevation of the cardiac PRPP pool. The decline in ATP that is induced in many pathophysiological conditions was attenuated or even entirely prevented by i.v. infusion of ribose. In two in vivo rat models, the overloaded and catecholamine-stimulated heart and the infarcted heart, the normalization of the cardiac adenine nucleotide pool by ribose was accompanied by an improvement of global heart function. Combination of ribose with adenine or inosine in isoproterenol-treated rats was more effective to restore completely the cardiac ATP level within a short period of time than either intervention alone.

Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH

“…It is, therefore, reasonable to speculate that, as a result of endothelial dysfunction, glucose is shunted through the PPP in the failing heart. Previous studies have shown that glucose is metabolized via the PPP in both healthy and diseased hearts (16,18,44,57,58). In the present study, we have shown that endothelial dysfunction and upregulated G6PD activity, in turn, leads to increased Noxcatalyzed O 2 Ϫ production in the hearts and aortas of obese, hyperglycemic, hyperinsulinemic, and hyperlipidemic rats.…”

“…Therefore, we and others have suggested that NADPH generated by glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP), fuels Nox and sustains O 2 Ϫ production in the heart (18,60) and vasculature (17,36). A small fraction of the total glucose in the cytosol of cardiomyocytes is oxidized to ribose by the PPP (57,58), and we recently demonstrated that overexpression of G6PD augments NADPH production, which increases O 2 Ϫ production by Nox in pacing-induced heart failure, an established model of dilated cardiomyopathy in dog (18), and in ischemic cardiomyopathy in humans (16). Likewise, several other investigators have reported carbohydrate and fatty acid metabolism to be profoundly altered in the nondiabetic failing heart (52).…”

Unique Metabolic Features of Stem Cells, Cardiomyocytes, and Their Progenitors

“…Alternatively, the glucose-6-phosphate (G6P) intermediate of the glycolytic pathway is capable of entering the pentose phosphate pathway in cardiomyocytes, thereby generating nicotinamide adenine dinucleotide phosphate (NADPH) and contributing to cardiomyocyte contractility. 115,130,131 It has been proposed that NADPH is crucial for the maintenance of the reduced glutathione and therefore acts protectively against the ROS-induced cell injury. 132 In good agreement with the above observation, G6P dehydrogenase (G6PD) lacking mice showed much more severe heart damage induced by the myocardial ischemia-reperfusion injury in Langendorff-perfused hearts as compared with wild-type mice.…”

Adaptation and Maladaptation of the Heart in Diabetes: Part II

“…76 In addition, pressure overload induces glucose 6-phosphate dehydrogenase (G6PDH), the enzyme catalyzing the flux generating step in the oxidative PPP. 77 It is therefore reasonable to assume that xylulose 5-phosphate levels increase in the hypertrophied heart due to the combined increase in glucose flux into the cardiomyocyte and increased G6PDH activity.…”