Nitric oxide signalling in cardiovascular health and disease, 2018, Farah et al

[SNT Gatchaman]

Nitric oxide signalling in cardiovascular health and disease
Charlotte Farah, Lauriane Y. M. Michel, Jean-Luc Balligand

Abstract
Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)–NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research.

In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability.

Key Points

• The three isoforms of nitric oxide synthase subserve distinct, but coordinated, functions through their subcellular confinement in cardiac and vascular cells
• The redox environment dictates the fate of nitric oxide and pathophysiological effects
• Multiple regulatory points of downstream effectors ensure signalling specificity and allow therapeutic modulation
• New techniques for monitoring nitric oxide bioavailability will allow efficient tailoring of treatment

PubMed | Link (paywalled)

 

[SNT Gatchaman]

Given recent findings of alterations in NO production/function in endothelial cells and glial cells in ME/CFS, this is likely to be a useful review paper. Despite being paywalled, hopefully it's OK to post the figures to allow for discussion. As you can imagine from the figures, the paper itself is quite dense.


Figure 1
NOS–NO signalling in cardiovascular tissues. In the vessel wall, nitric oxide (NO) synthesis by endothelial nitric oxide synthase (eNOS) in endothelial cells regulates vascular smooth muscle cell (VSMC) relaxation, mediates angiogenesis, inhibits VSMC proliferation, and through its diffusion to the vessel lumen inhibits platelet aggregation and thrombosis. S-nitrosylation of haemoglobin and/or reduction of nitrites (NO2−) by deoxyhaemoglobin promotes NO release and subsequent NO-mediated relaxation in hypoxic tissues. Diffusion and bioavailability of NO in VSMCs are regulated by haemoglobin-α (Hb-α) at the myoendothelial junction and by cytoglobin (CYGB) in muscle cells. Synthesis of NO by neuronal nitric oxide synthase (nNOS) within VSMCs also contributes to regulate vascular tone. In cardiac myocytes, autocrine and paracrine effects of NO from eNOS and nNOS modulate cardiac contractility through regulation of excitation–contraction coupling (including in response to stretch and β1-adrenergic stimulation), relaxation, and mitochondrial respiration. nNOS expression in cardiac nerves and postsynaptic eNOS modulate the ortho–parasympathetic balance towards reinforced parasympathetic (vagal) transmission leading to reduced heart rate.

β1, adrenergic receptor β1; ACh, acetylcholine; m2, muscarinic acetylcholine receptor m2; NA, noradrenaline; SNO, S-nitrosothiol; SR, sarcoplasmic reticulum; T-tubule, transverse-tubule.

 

[SNT Gatchaman]

Figure 3
NOS–NO pathway in vascular beds in health and disease.

 

[Sly Saint]

Cardiac nitric oxide scavenging: role of myoglobin and mitochondria

Abstract
Vascular production of nitric oxide (NO) regulates vascular tone. However, highly permeable NO entering the cardiomyocyte would profoundly impact metabolism and signalling without scavenging mechanisms. The purpose of this study was to establish mechanisms of cardiac NO scavenging. Quantitative optical studies of normoxic working hearts demonstrated that micromolar NO concentrations did not alter mitochondria redox state or respiration despite detecting NO oxidation of oxymyoglobin to metmyoglobin. These data are consistent with proposals that the myoglobin/myoglobin reductase (Mb/MbR) system is the major NO scavenging site. However, kinetic studies in intact hearts reveal a minor role (∼9%) for the Mb/MbR system in NO scavenging. In vitro, oxygenated mitochondria studies confirm that micromolar concentrations of NO bind cytochrome oxidase (COX) and inhibit respiration. Mitochondria had a very high capacity for NO scavenging, importantly, independent of NO binding to COX. NO is also known to quickly react with reactive oxygen species (ROS) in vitro. Stimulation of NO scavenging with antimycin and its inhibition by substrate depletion are consistent with NO interacting with ROS generated in Complex I or III under aerobic conditions. Extrapolating these in vitro data to the intact heart supports the hypothesis that mitochondria are a major site of cardiac NO scavenging.

Key points

• Cardiomyocyte scavenging of vascular nitric oxide (NO) is critical in maintaining normal cardiac function.
• Myoglobin redox cycling via myoglobin reductase has been proposed as a major NO scavenging site in the heart.
• Non-invasive optical spectroscopy was used to monitor the effect of NO on mitochondria and myoglobin redox state in intact beating heart and isolated mitochondria.
• These non-invasive studies reveal myoglobin/myoglobin reductase plays a minor role in cardiac NO scavenging.
• A high capacity for NO scavenging by heart mitochondria was demonstrated, independent of cytochrome oxidase binding but dependent on oxygen and high redox potentials consistent with generation of reactive oxygen species.

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP284446