Reciprocal Relationship Between Reactive Oxygen Species and Cyclooxygenase-2 and Vascular Dysfunction in Hypertension

Martínez-Revelles, Sonia; Avendaño, María Soledad; García-Redondo, Ana B.; Álvarez, Yolanda; Aguado, Ana M.; Pérez-Girón, José Vicente; García-Redondo, L.; Esteban, Vanesa; Redondo, Juan Miguel; Alonso, María J.; Briones, Ana M.; Salaíces, Mercedes

doi:10.1089/ars.2011.4335

Cited by 135 publications

(127 citation statements)

References 37 publications

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“…AngII treatment increased vasoconstrictor responses to phenylephrine in WT mice, as described, 12 but not in GRK2 +/− mice ( Figure 4A and 4B). Because AngII infusion decreases NO availability in aorta, 12 the lack of effect of AngII on phenylephrine responses in GRK2 +/− arteries might be related to a lesser decrease in NO.…”

Section: Grk2 Deficiency Improves Vascular Function and No Signaling supporting

confidence: 66%

“…Because AngII infusion decreases NO availability in aorta, 12 the lack of effect of AngII on phenylephrine responses in GRK2 +/− arteries might be related to a lesser decrease in NO. As shown in Figure 4C and 4D, the NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME; 100 µmol/L) enhanced phenylephrine contraction in GRK2 +/− aortas more than in WT vessels after AngII (dAUC WT, 59±7; GRK2 +/− , 237±31; P<0.05), suggesting that NO bioavailability after AngII was better preserved in GRK2 +/− aortas.…”

Section: Grk2 Deficiency Improves Vascular Function and No Signaling mentioning

confidence: 99%

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Increased Nitric Oxide Bioavailability in Adult GRK2 Hemizygous Mice Protects Against Angiotensin II–Induced Hypertension

et al. 2014

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369D ifferent receptors and signaling molecules are involved in the development of hypertension by hyper-contracting or hypo-dilating blood vessels in a deleterious manner and by affecting the structure and mechanical properties of vessels. Among them, the G protein-coupled receptor (GPCR) family is of outmost importance. Adrenergic receptors and other GPCRs, such as angiotensin II (AngII), endothelin-1 (ET-1), dopamine, and vasopressin receptors, are key for vascular physiopathology.1 AngII is a master regulator of vascular tone, and many animal models of hypertension are based on the chronic elevation of AngII levels.GPCRs become inactivated to different extents when agonist signals are persistent in time, a process termed desensitization. This process is regulated by G protein-coupled receptor kinases (GRKs), a family of serine/threonine kinases able to phosphorylate intracellular domains of the receptors and initiate their uncoupling from the G protein, and thus signal termination.2 Among the 7 GRK isoforms, GRK2 is the most abundant in vessels together with GRK5 and plays a determinant role in the control of systemic vascular responses.3,4 The levels and activity of the GRK2 isoform are increased in animal models of hypertension and in lymphocytes from young patients with hypertension.5 In addition, GRK2 mRNA levels, but not those of GRK3 or GRK5, increase in correlation with systolic blood pressure in humans.6 GRK2 downregulates the in vivo effects of key vasoconstrictor receptors, such as ET 7 and AngII 8 receptors and α1 D adrenoceptors.9 Therefore, the increase in vascular GRK2 could have represented a protective mechanism for adaptation against a hypertensive phenotype. However, transgenic mice overexpressing GRK2 in the vascular smooth muscle cells (VSMC) show increased resting blood pressure.8 Moreover, elevated GRK2 levels impair vasodilator β adrenoceptors responses in different tissues and animal Abstract-G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous serine/threonine protein kinase able to phosphorylate and desensitize the active form of several G protein-coupled receptors. Given the lack of selective inhibitors for GRK2, we investigated the effects elicited by GRK2 inhibition in vascular responses using global adult hemizygous mice (GRK2 +/− ). The vasodilator responses to acetylcholine or isoproterenol were increased in aortas and mesenteric resistance arteries from GRK2 +/− mice compared with wild-type (WT) littermates. After angiotensin II (AngII) infusion, GRK2 +/− mice were partially protected against hypertension, vascular remodeling, and mechanical alterations, even when resting basal blood pressures were not significantly different. AngII infusion also (1) increased GRK2 levels in WT but not in GRK2 +/− vessels; (2) increased vasoconstrictor responses to phenylephrine in WT but not in GRK2 +/− mice; and (3) decreased vasodilator responses to acetylcholine and vascular pAkt and eNOS levels more in WT than in GRK2 +/− animals. Vascular NO production and the modulation of vasoco...

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Section: Grk2 Deficiency Improves Vascular Function and No Signaling supporting

confidence: 66%

Section: Grk2 Deficiency Improves Vascular Function and No Signaling mentioning

confidence: 99%

Increased Nitric Oxide Bioavailability in Adult GRK2 Hemizygous Mice Protects Against Angiotensin II–Induced Hypertension

et al. 2014

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“…We also demonstrated the contribution of COX‐2 to BCAA‐induced contraction as the selective COX‐2 inhibitor celecoxib also abolished BCAA contractile responses in L‐NAME‐incubated arteries. Whether this effect was due to COX‐2‐derived prostanoids or to the reciprocal relationship between ROS and COX‐2 suggested previously,51, 52, 53, 54 is unknown. More importantly, our data demonstrate that this excessive O 2 ·− likely reacts with NO leading to increased peroxynitrite formation and nitrosylated proteins, decreased NO availability and in turn, endothelium dysfunction.…”

Section: Discussionmentioning

confidence: 93%

“…The reasons for the different contribution of mitochondria and NADPH oxidase to the different parameters are unknown and probably rely on a complex regulation of each response or a possible reciprocal relationship between both sources as described earlier 54, 55. Finally, other sources of O 2 ·− such as the uncoupled eNOS, COX‐2 or xanthine oxidase among others, cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Zhenyukh

González‐Amor

Rodrigues-Díez

et al. 2018

J Cellular Molecular Medi

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112

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Branched‐chain amino acids (BCAA: leucine, isoleucine and valine) are essential amino acids implicated in glucose metabolism and maintenance of correct brain function. Elevated BCAA levels can promote an inflammatory response in peripheral blood mononuclear cells. However, there are no studies analysing the direct effects of BCAA on endothelial cells (ECs) and its possible modulation of vascular function. In vitro and ex vivo studies were performed in human ECs and aorta from male C57BL/6J mice, respectively. In ECs, BCAA (6 mmol/L) increased eNOS expression, reactive oxygen species production by mitochondria and NADPH oxidases, peroxynitrite formation and nitrotyrosine expression. Moreover, BCAA induced pro‐inflammatory responses through the transcription factor NF‐κB that resulted in the release of intracellular adhesion molecule‐1 and E‐selectin conferring endothelial activation and adhesion capacity to inflammatory cells. Pharmacological inhibition of mTORC1 intracellular signalling pathway decreased BCAA‐induced pro‐oxidant and pro‐inflammatory effects in ECs. In isolated murine aorta, BCAA elicited vasoconstrictor responses, particularly in pre‐contracted vessels and after NO synthase blockade, and triggered endothelial dysfunction, effects that were inhibited by different antioxidants, further demonstrating the potential of BCAA to induce oxidative stress with functional impact. In summary, we demonstrate that elevated BCAA levels generate inflammation and oxidative stress in ECs, thereby facilitating inflammatory cells adhesion and endothelial dysfunction. This might contribute to the increased cardiovascular risk observed in patients with elevated BCAA blood levels.

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“…In recent years, studies have shown that ROS activate COX, and that COX and its products induce ROS generation. This reciprocal association was mainly identified in hypertensive conditions (123) and in endotoxic shock (197).…”

Section: Other Mechanisms: Testosterone and Ros Generation/oxidative mentioning

confidence: 86%

Reactive oxygen species: players in the cardiovascular effects of testosterone

Tostes

Carneiro

Carvalho

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Tostes RC, Carneiro FS, Carvalho MH, Reckelhoff JF. Reactive oxygen species: players in the cardiovascular effects of testosterone. Am J Physiol Regul Integr Comp Physiol 310: R1-R14, 2016. First published November 4, 2015 doi:10.1152/ajpregu.00392.2014.-Androgens are essential for the development and maintenance of male reproductive tissues and sexual function and for overall health and well being. Testosterone, the predominant and most important androgen, not only affects the male reproductive system, but also influences the activity of many other organs. In the cardiovascular system, the actions of testosterone are still controversial, its effects ranging from protective to deleterious. While early studies showed that testosterone replacement therapy exerted beneficial effects on cardiovascular disease, some recent safety studies point to a positive association between endogenous and supraphysiological levels of androgens/testosterone and cardiovascular disease risk. Among the possible mechanisms involved in the actions of testosterone on the cardiovascular system, indirect actions (changes in the lipid profile, insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system), as well as direct actions (modulatory effects on proinflammatory enzymes, on the generation of reactive oxygen species, nitric oxide bioavailability, and on vasoconstrictor signaling pathways) have been reported. This mini-review focuses on evidence indicating that testosterone has prooxidative actions that may contribute to its deleterious actions in the cardiovascular system. The controversial effects of testosterone on ROS generation and oxidant status, both prooxidant and antioxidant, in the cardiovascular system and in cells and tissues of other systems are reviewed. cardiovascular; prooxidant; antioxidant TESTOSTERONE 1 IS THE PREDOMINANT and most important androgen, playing a major role in the development of male reproductive tissues (130,135). "Androgen" is a broad term for any natural or synthetic compound that primarily influences the growth and development of the male reproductive system, including the activity of the accessory male sex organs and development of male secondary sex characteristics (21, 135). Androgens are also essential for health and well being, and their beneficial and stimulant effects have been known for a long time, since the seminal studies from Brown-Séquard in the nineteenth century 2 (22, 135): "ь ь ь in the seminal fluid, as secreted by the testicles, a substance or several substances exist which, entering the blood by resorption, have a most essential use in giving strength to the nervous system and to other parts ь ь ь ."Other androgens include androstenedione, 5␣-dihydrotestosterone (DHT), which is produced from testosterone by the enzyme 5␣-reductase, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and synthetic androgens in their many steroid ester variations (e.g., testosterone cypionate, decanoate, undecanoate, enant...

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Reciprocal Relationship Between Reactive Oxygen Species and Cyclooxygenase-2 and Vascular Dysfunction in Hypertension

Abstract: The excess of ROS from NAD(P)H Oxidase and/or mitochondria and the increased vascular COX-2/TP receptor axis act in concert to induce vascular dysfunction and hypertension.

Cited by 135 publications

References 37 publications

Increased Nitric Oxide Bioavailability in Adult GRK2 Hemizygous Mice Protects Against Angiotensin II–Induced Hypertension

Increased Nitric Oxide Bioavailability in Adult GRK2 Hemizygous Mice Protects Against Angiotensin II–Induced Hypertension

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Reactive oxygen species: players in the cardiovascular effects of testosterone

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