Pyridine nucleotide regulation of cardiac intermediary metabolism.
The pyridine nucleotides NAD(+) and NADP(+) play a pivotal role in regulating intermediary metabolism in the heart. The intracellular NAD(+)/NADH ratio controls flux through various dehydrogenase enzymes involved in both anaerobic and aerobic metabolism and also regulates posttranslational protein modification. The intracellular NADP(+)/NADPH ratio controls flux through the pentose phosphate pathway (PPP) and the polyol pathway, while also regulating ion channel function and oxidative stress. Not only does the NAD(+)/NADH ratio regulate the rates of ATP production, it can also modify energy substrate preference. For instance, in many forms of heart disease a greater contribution from fatty acids for oxidative energy metabolism increases fatty acid β-oxidation-derived NADH, which can activate pyruvate dehydrogenase (PDH) kinase isoforms that inhibit PDH and subsequent glucose oxidation. As such, novel therapies that overcome fatty acid β-oxidation-induced inhibition of PDH improve cardiac efficiency and subsequent function during ischemia/reperfusion and in heart failure. Furthermore, recent studies have implicated a pivotal role for increased PPP-derived NADPH in mediating oxidative stress observed in heart failure. In this article, we review the multiple actions of NAD(+)/NADH and NADP(+)/NADPH in regulating intermediary metabolism in the heart. A better understanding of the roles of NAD(+)/NADH and NADP(+)/NADPH in cellular physiology and pathology could potentially be used to exploit pyridine nucleotide modification in the treatment of a number of different forms of heart disease.
423 Heritage Medical Research Center, University of Alberta, Edmonton, Canada.
John R
JR
Ussher
Jagdip S
JS
Jaswal
Gary D
GD
Lopaschuk
D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000502:physiology*; D009249:NADP / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*
D009243:NAD; D009249:NADP