Role of circulating S-nitrosothiols in control of blood pressure.

The biological effects of nitric oxide (NO) are in large part mediated by S-nitrosylation of peptides and proteins to produce bioactive S-nitrosothiols (SNOs).1–3 The observation of abnormal SNO levels in numerous pathophysiological states2 suggests that dysregulation of SNO homeostasis may contribute to disease pathogenesis. For example, the hypotension of human sepsis is accompanied by increases in circulating levels of vasodilatory SNOs.3 Although such altered SNO levels may simply mirror NO production (eg, induction of inducible NO synthase in sepsis), they may also reflect changes specific to SNO biosynthesis and metabolism. Indeed, mice lacking a SNO-metabolizing enzyme are profoundly hypotensive under anesthesia.3 Thus, blood pressure is evidently regulated by both synthesis and turnover of SNOs. In this issue of Hypertension, Gandley et al4 extend this paradigm by proposing that a defect in SNO turnover contributes to the hypertension of preeclampsia. In the blood, S-nitrosoalbumin (SNO-albumin) and S-nitrosohemoglobin (SNO-Hb) constitute the major conduits for circulating NO bioactivity. Although both SNOs may influence blood pressure, they operate within distinct signaling circuits. SNO-Hb can be viewed as a principal regulator of SNO homeostasis, adaptively modulating NO chemistry to control NO bioactivity. SNO-Hb is formed by transfer of NO from heme-iron to Cys 93 thiol on T to R structural transition (oxygenation) of the hemoglobin tetramer.5 SNO-Hb associates with the red blood cell (RBC) membrane via an interaction with the cytoplasmic domain of anion-exchanger 1 protein (CDAE1, Band 3); on deoxygenation (R3T) transfer of the NO group from SNO-Hb to a cysteine thiol within CDAE1 supports export of RBC vasodilatory activity.6 SNO-Hb thus serves as an O2 sensor and O2-dependent transducer of NO bioactivity. In contrast, it appears that rather than transducing a specific signal, albumin operates as a buffer to maintain NO homeostasis.7 S-nitrosylation of albumin occurs at Cys347 via reactions—with NO or nitrosothiols—that are favored by design: specifically, both hydrophobic pockets in albumin (NO/O2 coupling) and bound copper (NO/metal redox coupling) may serve to generate nitrosylating species.8–10 Gandley et al4 make the case that the buffering function of SNO-albumin is impaired in preeclamptic patients, where the thiol of albumin acts as a sink for NO and thus, raises blood pressure. Nudler and colleagues9 have previously demonstrated that albumin can raise blood pressure independently of its oncotic effects: Redistribution of NO, from the tissues into the hydrophobic core of the protein, subserves S-nitrosylation and lowers the steady-state level of vasodilatory NO within the vascular smooth muscle.9 Accumulating evidence strongly suggests a role of SNOalbumin in mitigating cardiovascular risk. Elevated ( 2 mol/L) concentrations of plasma SNOs (of which SNO-albumin is the major constituent) portend adverse cardiovascular outcomes in patients with end-stage renal disease and correlate with elevated blood pressures.11 Plasma SNOs are also elevated in patients with hypercholesterolemia.12 Increases in SNO are correlated with an increase in plasma ceruloplasmin, a protein that is known to support SNO synthesis,13 and with a decline in ascorbate, a compound known to promote SNO degradation.14 Gandley et al4 proffer compelling evidence that SNO throughput, not level, is the key measure of NO bioactivity in plasma. They observe elevated levels of SNO-albumin in preeclamptic versus normal pregnancy plasma (7 mol/L versus 2 mol/L, respectively) and link reduced levels of ascorbate in preeclampsia to impaired SNO-albumin–dependent vasorelaxation.4 (Notably, SNO-albumin is elevated in preeclampsia despite factors that might be assumed to abrogate the formation of nitrosothiols, including a well characterized oxidative stress and deficit of endothelial-derived NO.) Excessive sequestration of SNOs also occurs in patients with type I diabetes mellitus.15 In this case, however, hemoglobin is the culprit. Accumulation of SNO-Hb in diabetes has been attributed to glycosylation of Hb, which preferentially stabilizes the R structure, thereby impairing NO group release. Reduced vasodilation by diabetic RBCs has been implicated in the microvascular flow impairment associated with the disease. Hypoxic vasodilatory activity of RBCs is also impaired in other disorders of heart, lung, and blood,2,16 consistent with the idea that RBCs regulate blood flow to maximize O2 delivery.16–18 Accumulations of SNO-Hb can also raise blood pressure. This effect, however, occurs through some central action rather than through peripheral vasoconstriction. Comparable levels of plasma hemoglobin (micromolar) have no pressor effects,19 despite the frequent claims to the contrary.20 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Howard Hughes Medical Institute (M.W.F., J.S.S.), and Departments of Medicine (J.R.P., J.S.S.) and Biochemistry (J.S.S.), Duke University Medical Center, Durham, NC; and the Department of Chemistry and Biochemistry (D.J.S.), Montana State University, Bozeman, Mont. Correspondence to Jonathan S. Stamler, MD, Department of Medicine, Box 2612, Duke University Medical Center, Durham, NC 27710. Email [email protected] (Hypertension. 2005;45:000-000.) © 2004 American Heart Association, Inc.