S-nitrosylation: integrator of cardiovascular performance and oxygen delivery
Saptarsi M. Haldar, Jonathan S. Stamler
Saptarsi M. Haldar, Jonathan S. Stamler
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(1):101-110. https://doi.org/10.1172/JCI62854.
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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 2

S-nitrosylation regulates cardiomyocyte signaling at critical oxygen-responsive nodal points.

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S-nitrosylation regulates cardiomyocyte signaling at critical oxygen-re...
The central roles are highlighted for the denitrosylase GSNOR in physiologic control of β2-AR signaling, SR calcium release, HIF-1α responses, and mitochondrial function. S-nitrosylation reactions that have been proven by genetic criteria to occur through the intermediacy of GSNO include those targeting GRK2, RYR2, and HIF-1α. Ligand-dependent S-nitrosylation of GRK2, β-arrestin2, and dynamin is eNOS dependent. eNOS is complexed with GRK2, β-arrestin2, and dynamin, as depicted. Coordinate titration of S-nitrosylation (envisioned via receptor-coupled activity of transnitrosylases and denitrosylases) across multiple steps in these pathways determine net signaling responses. The effects of GSNOR (from observations in GSNOR–/– mice) manifest as increases in cardiac output under basal conditions, a persistent state of systemic vasodilation, and protection from ischemic insult, establishing a central role for GSNO in cardiovascular hemodynamics and oxygen delivery. Effects of GSNOR on mitochondrial targets are inferred from studies using GSNO. HRE, hypoxia response element.