Oxidative Stress and Human Hypertension: Vascular Mechanisms, Biomarkers, and Novel Therapies

doi:10.1016/j.cjca.2015.02.008

Canadian Journal of Cardiology

Volume 31, Issue 5, May 2015, Pages 631-641

https://doi.org/10.1016/j.cjca.2015.02.008 Get rights and content

Abstract

Hypertension is a major cardiovascular risk factor. Of the many processes involved in the pathophysiology of hypertension, vascular damage due to oxidative stress (excess bioavailability of reactive oxygen species [ROS]) is particularly important. Physiologically, ROS regulate vascular function through redox-sensitive signalling pathways. In hypertension, oxidative stress promotes endothelial dysfunction, vascular remodelling, and inflammation, leading to vascular damage. Vascular ROS are derived primarily by nicotinamide adenine dinucleotide phosphate oxidases, which are prime targets for therapeutic development. Although experimental evidence indicates a causative role for oxidative stress in hypertension, human data are less convincing. This might relate, in part, to suboptimal methods to accurately assess the redox state. Herein we review current knowledge on oxidative stress in vascular pathobiology and implications in human hypertension. We also discuss biomarkers to assess the redox state in the clinic, highlight novel strategies to inhibit ROS production, and summarize how lifestyle modifications promote vascular health by reducing oxidative stress.

Résumé

L'hypertension est un facteur de risque cardiovasculaire majeur. Parmi les nombreux processus intervenant dans la physiopathologie de l'hypertension, les lésions vasculaires dues au stress oxydatif (biodisponibilité excessive des espèces réactives de l'oxygène [ERO]) sont particulièrement importantes. Physiologiquement, les ERO régulent la fonction vasculaire par les voies de signalisation sensibles à l’état redox. Dans l'hypertension, le stress oxydatif qui favorise la dysfonction endothéliale, le remodelage vasculaire et l'inflammation entraîne les lésions vasculaires. Les ERO vasculaires proviennent principalement des oxydases du nicotinamide-adénine-dinucléotide-phosphate, qui sont les cibles de choix du développement thérapeutique. Bien que les données probantes expérimentales montrent que le stress oxydatif joue un rôle causal dans l'hypertension, les données sur l’être humain sont moins convaincantes. Cela pourrait en partie avoir un lien avec les méthodes qui sont sous-optimales pour évaluer avec précision l’état redox. Ici, nous passons en revue les connaissances actuelles sur la pathobiologie vasculaire et les conséquences liées au stress oxydatif sur l'hypertension chez les êtres humains. Nous discutons également des biomarqueurs pour évaluer l’état redox en clinique, soulignons les nouvelles stratégies pour inhiber la production d’ERO et résumons comment les modifications au mode de vie favorisent la santé vasculaire en réduisant le stress oxydatif.

Section snippets

Oxidative Stress and ROS: A Brief Overview

The notion of “oxidative stress” was originally defined by Sies in 1985 as an imbalance between pro-oxidants and antioxidants, with consequent increased ROS bioavailability, which leads to tissue damage.¹⁸ Since then it has become clear that ROS, at appropriate concentrations and in defined subcellular localizations, also play an important physiological role in cellular signalling, regulation of cell growth and differentiation, vascular tone, inflammation, and immune responses.¹⁹ Accordingly,

Redox Signalling and Vascular Biology in Hypertension

To appreciate how ROS regulate signalling and vascular function, it is important to know how ROS influence protein activity and cell function (Fig. 2).²⁴ Briefly, proteins that contain cysteine residues are highly sensitive to oxidative modification. These oxidative modifications lead to changes in structure, activity, and function of target proteins. Proteins that are redox-sensitive include ion transporters, receptors, kinases, phosphatases, transcription factors, structural proteins, and

Production and Metabolism of Vascular ROS

In vessels ROS are produced primarily by nonphagocytic NADPH oxidase (Nox), although other enzymatic sources might also contribute, such as xanthine oxidase, mitochondrial electron transport chain, uncoupled endothelial NO synthase (eNOS), COX, lipoxygenase, and cytochrome P450 oxidases.34, 40, 41, 42, 43, 44 In human hypertension, Nox and xanthine oxidase appear to be most important in the vasculature.

Oxidative Stress in Human Hypertension

Clinical studies in patients with essential hypertension demonstrated that systolic and diastolic blood pressure correlate positively with biomarkers of oxidative stress and negatively with antioxidant levels.65, 66, 67, 68, 69, 70, 71 Endothelial dysfunction, a hallmark of the vascular phenotype in hypertension, is associated with increased vascular ROS production, oxidative stress, and vascular inflammation. This is evidenced by an inverse association between acetylcholine-dependent

Role of Nox and ROS in Vascular Function in Humans: Direct Evidence

Most studies on the role of ROS in vascular pathobiology and essential hypertension have focused primarily on associative links where indices of oxidative stress and vascular injury are positively related to blood pressure. More direct evidence indicating an important role for ROS in vascular function is derived from studies in patients with chronic granulomatous disease (CGD) who have mutations of Nox subunits and a consequent reduction in ROS generation.75, 76 In patients with CGD,

Biomarkers of Oxidative Stress in Human Hypertension

ROS are unstable and have a very short half-life. Hence, accurately assessing O₂^−• and H₂O₂ in the clinic is challenging. As such, methods have been developed to measure stable markers of ROS that reflect oxidative status. Biomarkers of oxidative stress that are currently used to assess redox state in human samples are oxidation products of lipids, DNA, and protein.78, 79

Targeting Oxidative Stress as a Therapeutic Strategy in Human Hypertension

If oxidative stress is indeed involved in the development of hypertension, then reducing oxidative damage by scavenging ROS with antioxidants and/or reducing the production of ROS should ameliorate vascular injury and decrease blood pressure.

BH4

Optimizing eNOS function and reducing ONOO− production might be an attractive approach to treating endothelial dysfunction and hypertension. This can be achieved by cofactors BH4, or substrate L-arginine, or by increasing cyclic guanosine monophosphate availability via phosphodiasterase 5 inhibitors. BH4, a cofactor for NO synthesis is a potentially interesting therapeutic target in the endothelium. In hypertensive patients infused with BH4 intra-arterially, endothelial function was

Conclusions

Physiologically, ROS play an important role in regulating vascular function through tightly controlled redox-sensitive signalling pathways. Uncontrolled production/degradation of ROS results in oxidative stress, which induces vascular injury with associated increases in systemic blood pressure. Convincing evidence from experimental and animal studies indicate a causative role for oxidative stress and ROS-generating Nox in the pathogenesis of hypertension. However, in humans it is still unclear

Funding Sources

Work from the author's laboratory was supported by grants 44018 and 57886 from the Canadian Institutes of Health Research (CIHR) and grants from the British Heart Foundation (BHF). R.M.T. is supported through a BHF Chair. A.C.M. is supported through a Leadership Fellowship from the University of Glasgow. A.M.B. is supported by the Ramón y Cajal Program (RyC-2010-06473).

Disclosures

The authors have no conflicts of interest to disclose.

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ReviewOxidative Stress and Human Hypertension: Vascular Mechanisms, Biomarkers, and Novel Therapies

Abstract

Résumé

Section snippets

Oxidative Stress and ROS: A Brief Overview

Redox Signalling and Vascular Biology in Hypertension

Production and Metabolism of Vascular ROS

Oxidative Stress in Human Hypertension

Role of Nox and ROS in Vascular Function in Humans: Direct Evidence

Biomarkers of Oxidative Stress in Human Hypertension

Targeting Oxidative Stress as a Therapeutic Strategy in Human Hypertension

BH4

Conclusions

Funding Sources

Disclosures

Lancet

Am J Clin Nutr

Chem Biol Interact

Redox Biol

Cell Signal

Redox Biol

Free Radic Biol Med

J Biol Chem

Microvasc Res

Free Radic Biol Med

Am J Pathol

Redox Biol

Transl Res

Trends Biochem Sci

Mol Aspects Med

Free Rad Biol Med

Free Radic Biol Med

Biochim Biophys Acta

Nutr Metab Cardiovasc Dis

Free Radic Biol Med

Redox Biol

J Mol Cell Cardiol

Biochim Biophys Acta

Chem Phys Lipids

Diabetes Res Clin Pract

Hypertension: a global perspective

Circulation

Modelling the impact on avoidable cardiovascular disease burden and costs of interventions to lower SBP in the England population

J Hypertens

Angiotensin II and the vascular phenotype in hypertension

Expert Rev Mol Med

Angiotensin II and vascular injury

Curr Hypertens Rep

New paradigms in inflammatory signaling in vascular endothelial cells

Am J Physiol Heart Circ Physiol

Vascular remodeling in hypertension: mechanisms and treatment

Hypertension

Endothelial cells negatively modulate reactive oxygen species generation in vascular smooth muscle cells: role of thioredoxin

Hypertension

Angiotensin II, from vasoconstrictor to growth factor: a paradigm shift

Circ Res

NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis

Circulation

Angiotensin II, NADPH oxidase, and redox signaling in the vasculature

Antioxid Redox Signal

Role of mitochondrial oxidative stress in hypertension

Am J Physiol Heart Circ Physiol

Oxidative stress in hypertension: role of the kidney

Antioxid Redox Signal

Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms

Clin Sci (Lond)

Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies

Ann Med

Antioxidants in hypertension and cardiovascular disease

Mol Interv

Redox pioneer: professor Helmut Sies

Antioxid Redox Signal

Redefining oxidative stress

Antioxid Redox Signal

Thiol/disulfide redox states in signaling and sensing

Crit Rev Biochem Mol Biol

Redox compartmentalization and cellular stress

Diabetes Obes Metab

Radical-free biology of oxidative stress

Am J Physiol Cell Physiol

Review
Oxidative Stress and Human Hypertension: Vascular Mechanisms, Biomarkers, and Novel Therapies