S-nitrosylation: integrator of cardiovascular performance and oxygen delivery
Saptarsi M. Haldar, Jonathan S. Stamler
Saptarsi M. Haldar, Jonathan S. Stamler
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S-nitrosylation: integrator of cardiovascular performance and oxygen delivery

Abstract

Delivery of oxygen to tissues is the primary function of the cardiovascular system. NO, a gasotransmitter that signals predominantly through protein S-nitrosylation to form S-nitrosothiols (SNOs) in target proteins, operates coordinately with oxygen in mammalian cellular systems. From this perspective, SNO-based signaling may have evolved as a major transducer of the cellular oxygen-sensing machinery that underlies global cardiovascular function. Here we review mechanisms that regulate S-nitrosylation in the context of its essential role in “systems-level” control of oxygen sensing, delivery, and utilization in the cardiovascular system, and we highlight examples of aberrant S-nitrosylation that may lead to altered oxygen homeostasis in cardiovascular diseases. Thus, through a bird’s-eye view of S-nitrosylation in the cardiovascular system, we provide a conceptual framework that may be broadly applicable to the functioning of other cellular systems and physiological processes and that illuminates new therapeutic promise in cardiovascular medicine.

Authors

Saptarsi M. Haldar, Jonathan S. Stamler

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Figure 1

Framework for PTMs and signaling.

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Framework for PTMs and signaling. (A) Parallels between S-nitrosylation ...
(A) Parallels between S-nitrosylation and other PTMs (phosphorylation, ubiquitinylation, and acetylation) highlight shared features of bona fide signaling systems. S-nitrosylation is ubiquitous, reversible, and subject to enzymatic control (by nitrosylases and denitrosylases), enabling spatiotemporal and target specificity. The biochemistry of NO group transfer and denitrosylation reactions is depicted. Note that auto–S-nitrosylation is shown as an example of metal-to-Cys NO transfer (e.g., as occurs from the Hb heme center to Cysβ93 to form SNO-Hb). However, metal-to-Cys NO transfer between two different peptides or proteins may also occur (e.g., between cytochrome C and glutathione to form GSNO). (B) Denitrosylases. Two classes of denitrosylases are shown, which comprise four enzymes in mammals, including two GSNORs and two thioredoxins. GR, glutathione reductase; GSH, reduced glutathione; GSNHOH, glutathione N-hydroxysulfenamide; GSSG, oxidized glutathione; TrxR, Trx reductase.