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Strategies to increase nitric oxide signalling in cardiovascular disease

Nature Reviews Drug Discovery volume 14, pages 623–641 (2015)Cite this article

Subjects

Key Points

  • Nitric oxide (NO), a diatomic free radical gas, is generated by NO synthases (NOSs) in tissues to regulate a multitude of physiological processes, most notably cardiovascular function.

  • A decrease in the formation and bioavailability of NO is a hallmark of several cardiovascular diseases.

  • Traditional ways of increasing NO levels — with nitroglycerin or other organic nitrates — have limited clinical utility, mainly owing to unfavourable pharmacokinetics and the development of tolerance.

  • Several alternative strategies to increase NO signalling in the cardiovascular system have recently emerged, with promising therapeutic potential.

  • These strategies include the identification of novel pathways for enhancing NOS activity, amplification of the nitrate–nitrite–NO pathway, novel classes of NO-donating drugs, drugs that limit NO metabolism using reactive oxygen species, and modulation of downstream phosphodiesterases and soluble guanylyl cyclases.

Abstract

Nitric oxide (NO) is a key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and disease are well characterized. Although early approaches to therapeutically modulate NO bioavailability failed in clinical trials, an enhanced understanding of fundamental subcellular signalling has enabled a range of novel therapeutic approaches to be identified. These include the identification of: new pathways for enhancing NO synthase activity; ways to amplify the nitrate–nitrite–NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream phosphodiesterases and soluble guanylyl cyclases. In this Review, we discuss these latest developments, with a focus on cardiovascular disease.

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Figure 1: Diseases and lifestyle factors associated with reduced bioavailability of nitric oxide.
Figure 2: Vascular nitric oxide signalling in health and disease.
Figure 3: Key reactions of nitric oxide that contribute to its diverse signalling properties.
Figure 4: Proposed mechanisms for the cardioprotective effects of nitric oxide.
Figure 5: Targets for increasing nitric oxide bioavailability in the vasculature.
Figure 6: Mechanisms by which dietary polyphenols can increase the bioavailability of nitric oxide in the cardiovascular system.

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Acknowledgements

The authors wish to sincerely thank all co-authors of the original articles from their groups, which are highlighted in this Review. A special thanks to J. Lancaster Jr for valuable comments on the manuscript. J.O.L. and E.W. receive research support from Torsten Söderbergs Foundation, Jochnick Foundation, the Swedish Research Council, the Swedish Heart and Lung Foundation and Stockholm County Council (ALF). M.T.G. receives research support from US National Institutes of Health (NIH; grants 2R01HL098032, 1R01HL125886-01, P01HL103455, T32 HL110849 and T32 HL007563), the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, SE-171 77, Sweden

    Jon O. Lundberg & Eddie Weitzberg

  2. Vascular Medicine Institute, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, 15213, Pennsylvania, USA

    Mark T. Gladwin

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  1. Jon O. Lundberg
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Correspondence to Jon O. Lundberg, Mark T. Gladwin or Eddie Weitzberg.

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Competing interests

J.O.L. and E.W. are co-inventors of patent applications relating to the medical uses of inorganic nitrate and nitrite salts and co-directors of Heartbeet Ltd. M.T.G. is listed as a co-inventor on a US National Institutes of Health government patent for the use of nitrite salts in cardiovascular diseases. M.T.G. also receives grant support from Aires Pharmaceuticals (now owned by Molecular Adhesion and Sealant Technology (MAST) Therapeutics) for a Phase II proof-of-concept trial using inhaled nitrite for pulmonary arterial hypertension.

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Glossary

Organic nitrates

A group of synthetic pharmacological substances used in the treatment of cardiovascular disease. They are esters of nitric acid that contain an organic carbon residue and a nitrooxyl group (ONO2). Organic nitrates are enzymatically metabolized to generate nitric oxide and nitrite.

Vascular endothelium

A layer of cells that covers the inner surface of the vasculature and acts as a bioactive interface between the blood and the vascular wall. The endothelium is involved in many aspects of vascular biology by generating substances to uphold vascular homeostasis and in the control of vascular tone.

Phosphorylation

The addition of a phosphate group (PO43−) to a protein or other organic compound, thereby regulating its function and activity. This important mechanism is enzymatically regulated by kinases (which phosphorylate proteins) and phosphatases (which dephosphorylate proteins).

Superoxide

A reactive free radical that is constantly produced in the human body through the reduction of molecular oxygen. The main systems that generate superoxide in the body are NADPH oxidases, mitochondria and xanthine oxidoreductase. Physiological generation of superoxide is important for cell signalling, but increased production leads to oxidative stress.

Atherosclerosis

A progressive, inflammatory process characterized by the build-up of fats, cholesterol and other substances in the artery wall (plaques) that can restrict blood flow. Plaque rupture in the coronary vasculature leads to acute myocardial infarction.

Cyclic guanosine monophosphate

(cGMP). A cyclic nucleotide derived from GTP that acts as a second messenger, much like cyclic AMP.

Free radical

A molecule or ion that has an unpaired valence electron, which makes it chemically reactive with other substances. Examples relevant to this article are nitric oxide (NO) and superoxide (O2−).

Transition metals

A group of elements in the periodic system. They are important in biological chemistry owing to their ability to exhibit two or more oxidation states. Examples include iron, cobalt, copper and molybdenum, of which iron is the most important because of its involvement in oxygen transport and electron transfer reactions (that is, oxidation–reduction reactions). Molybdenum-containing enzymes are involved in the reduction of nitrate to nitrite (NO3− to NO2−) and nitrite to nitric oxide (NO2− to NO).

Reactive oxygen species

(ROS). Molecules that are highly reactive owing to the presence of unpaired valence-shell electrons. ROS form as a natural by-product of the normal metabolism of oxygen and have important roles in cell signalling; however, increased ROS levels can result in substantial damage to cell structures (known as oxidative stress).

Methaemoglobin

A form of the oxygen-carrying protein haemoglobin in which the iron in the haem group is in the Fe3+ state rather than the Fe2+ state of normal haemoglobin. Methaemoglobin is unable to carry oxygen.

Cytochrome c oxidase

The final component in the mitochondrial respiratory chain, which catalyses the reduction of oxygen, leading to build up of a chemiosmotic gradient used for ATP production.

Ischaemic preconditioning

A technique for producing tissue protection against the loss of blood flow to an organ by inducing short, repeated episodes of ischaemia before an ischaemic insult, which reduces subsequent tissue injury.

Inotropic

Affecting the force of muscle contractions in the heart.

Ischaemia–reperfusion injury

(I–R injury). Tissue damage caused during organ reperfusion after a period of ischaemia. Restoration of blood flow results in inflammation and oxidative stress.

Mitochondrial electron transport chain

A system that transports electrons from energy-rich electron donors and pumps protons across the inner mitochondrial membrane, building an electrochemical gradient that is used to generate ATP, the energy currency for all biochemical processes.

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Lundberg, J., Gladwin, M. & Weitzberg, E. Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14, 623–641 (2015). https://doi.org/10.1038/nrd4623

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