Pathophysiological aspects of cellular pyridine nucleotide metabolism: focus on the vascular endothelium. Review.
In recent years, pyridine nucleotides NAD(H) and NADP(H) have been established as an important molecules in physiological and pathophysiological signaling and cell injury pathways. Protein modification is catalyzed by ADP-ribosyl transferases that attach the ADP-ribose moiety of NAD+ to specific aminoacid residues of the acceptor proteins, with significant changes in the function of these acceptors. Mono(ADP-ribosyl)ation reactions have been implicated to play a role both in physiological responses and in cellular responses to bacterial toxins. Cyclic ADP-ribose formation also utilizes NAD+ and primarily serves as physiological, signal transduction mechanisms regulating intracellular calcium homeostasis. In pathophysiological conditions associated with oxidative stress (such as various forms of inflammation and reperfusion injury), activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) occurs, with subsequent, substantial fall in cellular NAD+ and ATP levels, which can determine the viability and function of the affected cells. In addition, NADPH oxidases can significantly affect the balance and fate of NAD+ and NADP in oxidatively stressed cells and can facilitate the generation of various positive feedback cycles of injury. Under severe oxidant conditions, direct oxidative damage to NAD+ has also been reported. The current review focuses on PARP and on NADPH oxidases, as pathophysiologically relevant factors in creating disturbances in the cellular pyridine nucleotide balance. A separate section describes how these mechanisms apply to the pathogenesis of endothelial cell injury in selected cardiovascular pathophysiological conditions.
Szabó
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Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary. szabocsaba@aol.com
D036002:ADP Ribose Transferases / Q000378:metabolism; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008954:Models, Biological; D009243:NAD / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D009243:NAD; D009249:NADP; D019255:NADPH Oxidases; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases