Pyridine nucleotide regulation of cardiac intermediary metabolism.

Abstract

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.

• Authors: John R Ussher, Jagdip S Jaswal, Gary D Lopaschuk
• Journal: Circulation research (Circ Res) Vol. 111 Issue 5 Pg. 628-41 (Aug 17 2012) ISSN: 1524-4571 [Electronic] United States
• PMID: 22904042 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• NAD
• NADP

Topics

• Animals
• Energy Metabolism (physiology)
• Humans
• Myocardium (metabolism)
• NAD (physiology)
• NADP (physiology)
• Oxidative Stress (physiology)