Nitric-oxide-induced vasodilatation: regulation by physiologic s-glutathiolation and pathologic oxidation of the sarcoplasmic endoplasmic reticulum calcium ATPase.
Nitric-oxide (NO)-induced vasodilatation is impaired in patients with a variety of cardiovascular diseases. Cyclic GMP, the principal mediator of NO-induced smooth muscle relaxation, usually functions normally, and the impairment in endothelial-mediated vasodilatation is attributed to increased oxidants that diminish NO bioactivity. In investigating the mechanisms involved, we found that independently of cyclic GMP, NO stimulates the uptake of cytosolic Ca(2+) via the sarcoplasmic reticulum Ca(2+) ATPase (SERCA), thereby relaxing vascular smooth muscle by lowering intracellular free Ca(2+). Nitric oxide was found to do so by reacting with superoxide to form peroxynitrite, which in turn caused glutathione (GSH) to bind to SERCA cysteine thiols. Most of the GSH was bound to the most reactive thiol on SERCA cysteine-674, and mutation of this residue prevented stimulation of Ca(2+) uptake by NO. In atherosclerotic arteries, we found that NO no longer stimulated SERCA activity because of the irreversible oxidation of the cysteine-674 thiol. These studies not only demonstrate a novel mechanism of NO-induced vasodilatation, but also provide an explanation as to how chronically increased levels of oxidants associated with disease impair vasodilatation in diseased arteries.
Cohen
Richard A
RA
Vascular Biology Unit, Robert Dawson Evans Department of Medicine, Boston University Medical Center, 650 Albany Street, Boston, MA 02118, USA. racohen@bu.edu
Adachi
Takeshi
T
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D045462:Endothelium-Dependent Relaxing Factors; D009569:Nitric Oxide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D005978:Glutathione