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Review
. 2021 Apr 2;128(7):993-1020.
doi: 10.1161/CIRCRESAHA.121.318063. Epub 2021 Apr 1.

Oxidative Stress and Hypertension

Kathy K Griendling  1 , Livia L Camargo  2 , Francisco J Rios  2 , Rhéure Alves-Lopes  2 , Augusto C Montezano  2 , Rhian M Touyz  2
Affiliations
Review

Oxidative Stress and Hypertension

Kathy K Griendling et al. Circ Res. .

Abstract

A link between oxidative stress and hypertension has been firmly established in multiple animal models of hypertension but remains elusive in humans. While initial studies focused on inactivation of nitric oxide by superoxide, our understanding of relevant reactive oxygen species (superoxide, hydrogen peroxide, and peroxynitrite) and how they modify complex signaling pathways to promote hypertension has expanded significantly. In this review, we summarize recent advances in delineating the primary and secondary sources of reactive oxygen species (nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, endoplasmic reticulum, and mitochondria), the posttranslational oxidative modifications they induce on protein targets important for redox signaling, their interplay with endogenous antioxidant systems, and the role of inflammasome activation and endoplasmic reticular stress in the development of hypertension. We highlight how oxidative stress in different organ systems contributes to hypertension, describe new animal models that have clarified the importance of specific proteins, and discuss clinical studies that shed light on how these processes and pathways are altered in human hypertension. Finally, we focus on the promise of redox proteomics and systems biology to help us fully understand the relationship between ROS and hypertension and their potential for designing and evaluating novel antihypertensive therapies.

Keywords: antioxidants; biomarkers; endoplasmic reticulum stress; hydrogen peroxide; reactive oxygen species.

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Conflict of interest statement

CONFLICTS TO DECLARE

There are no conflicts to declare.

Figures

Figure 1.
Figure 1.. Sources of ROS in the cardiovascular system.
The major soure of ROS in the cardioavscular system is the Nox family. Nox1–4 are p22phox-dependent oxidases, whereas Nox5, a Ca2+-sensitive Nox, does not require p22phox for its activation. In the cardiovascular system, Noxes are regulated by pro-hypertensive and inflammatory factors including Ang II, ET-1, aldosterone, salt, growth factors (VEGF, EGF) and TNF. ROS are also generated by eNOS uncoupling, and mitochondrial and ER mechanisms, which are influenced by Nox/ROS. MR, mineralocorticoid receptor; AT1R, Ang II type 1 receptor; ETAR, ET-1 type A receptor; GFR, growth factor receptor; BH4, tetrahydrobiopterin.
Figure 2.
Figure 2.. Interplay between oxidative stress and ER stress in hypertension.
Increased Nox-induced ROS generation promotes activation of ER stress signaling pathways and the unfolded protein response that influence vascular function in hypertension.
Figure 3.
Figure 3.. Post translational oxidative modification of proteins.
Main reactions leading to reversible and irreversible oxidation of proteins in cardiovascular cells.
Figure 4.
Figure 4.. Schematic of redox-sensitive signaling pathways involved in hypertension.
ROS influence many signaling molecules that regulate cardiovascular function including kinases, phosphatases, Ca2+ channels, transcription factors, genes. These processes involve oxidative post-translational modifications (Ox-PTM) of downstream redox-sensitive targets. Oxidative stress causes abnormal redox signaling leading to cardiovascular dysfunction and remodeling in hypertension. Decreased antioxidants contribute to oxidative stress. PTP, protein tyrosine phosphatases; MMP, matrix metalloproteinases; UPR, unfolded protein response.
Figure 5.
Figure 5.. Oxidative stress and the inflammasome in hypertension.
Prohypertensive factors induce activation of NLRP3 inflammasome through ROS. ROS influences signal 1 (cytokines, pathogen-associated molecular patterns (PAMPS), danger-associated molecular patterns (DAMPS)), leading to activation of NFkB and gene expression of components of the inflammasome. ROS also influence signal 2, by PAMPS, DAMPS, oxidized LDL (oxLDL), oxidized phospholipids (oxPL), ATP, Ang II, ET-1, aldosterone (aldo) and cations (K+, Ca2+, Na+). These processes lead to assembly of the inflammasome complex (NLRP3, ASC and pro-caspase 1), and consequent activation of caspase 1, cleavage of pro-IL-1β and pro-IL-18, and production of active forms of IL-1β and IL-18, which increase the inflammatory response, fibrosis and vascular remodelling in hypertension. MR, mineralocorticoid receptor; ASC - Apoptosis-Associated Speck-Like Protein Containing CARD; question mark (?) indicates possible effect.
Figure 6.
Figure 6.. Systems biology, oxidative stress and hypertension.
Functional effects of oxidative stress in regulatory systems and organs in the pathophysiology of hypertension.
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