Signaling pathways involved in the H2O2-induced vasoconstriction of rat coronary arteries

Santiago, Elvira; Contreras, Cristina; García‐Sacristán, Albino; Sánchez, Ana; Rivera, Luis; Climent, Belén; Prieto, Dolores

doi:10.1016/j.freeradbiomed.2013.02.014

Cited by 33 publications

(47 citation statements)

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“…ERK1/2 participates in the H 2 O 2 contractile response in different vessels from normotensive animals [19,22]. In addition, Tabet et al [23] described that H 2 O 2 induced ERK1/2 activation in cultured VSMC from SHR and WKY.…”

Section: Role Of Erk1/2mentioning

confidence: 99%

c-Src, ERK1/2 and Rho kinase mediate hydrogen peroxide-induced vascular contraction in hypertension

García-Redondo

Briones

Martínez-Revelles

et al. 2015

Journal of Hypertension

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Abstract:Aim: to analyze the signaling pathways involved in H₂O₂ vascular responses in hypertension. Methods: Vascular function, thromboxane A₂ (TXA₂) production, oxidative stress and protein expression were determined in mesenteric resistance arteries (MRA) from hypertensive (SHR) and normotensive WKY rats. Results: H₂O₂ and the TP agonist U46619 induced greater contractile responses in MRA from SHR than WKY. Moreover H₂O₂increased TXA₂production more in SHR than in WKY. The cSrc inhibitor PP1 reduced H₂O₂-and U46619-induced contraction and TXA₂ release in both strains. The ERK1/2 inhibitor PD98059 reduced H₂O₂but not U46619-induced contraction only in SHR arteries. The Rho Kinase inhibitor Y26372 reduced H₂O₂and U46619-induced contractions only in SHR arteries. Basal c-Src, ERK1/2 and Rho Kinase expression were greater in MRA from SHR than WKY. In SHR, the combination of PD98059 with the TP antagonist SQ29548 but not with Y27632, inhibited the H₂O₂contraction more than each inhibitor alone. H₂O₂and U46619 increased NAD(P)H Oxidase activity and O₂.-production and decreased mitochondrial membrane potential in vessels from SHR. The effects induced by H₂O₂were abolished by inhibitors of TXA₂synthase, ERK1/2 and c-Src. The mitochondrial antioxidant mitoTEMPO reduced H₂O₂-induced contraction and NAD(P)H Oxidase activation. Conclusions: In arteries from WKY, c-Src mediates H₂O₂ contractile responses by modulating TXA₂release and TXA₂ effect. In SHR, H₂O₂contraction is mediated by c-Src-dependent TXA₂ release which further activates Rho Kinase, c-Src and the relationship between mitochondria and NAD(P)H Oxidase. Moreover, ERK1/2 activation contributes to H₂O₂ contraction in SHR through effects on mitochondria/NAD(P)H Oxidase. We affirm that the present study is not under consideration by another journal, and that no part of the material has been published elsewhere. All persons acknowledged have seen and approved the mention of their name in the paper. We also state that there is no conflict of interest. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationWe hope that the new version of the manuscript fulfills all the requirements for its publication Answers to Reviewer 1We would like to thank the Reviewer for his/her constructive comments. The manuscript has undergone changes to include data from new experiments. All concerns raised have been addressed and a detailed list of changes made is attached. We believe that the paper is significantly improved and hope that it is now acceptable for publication. I have no major concerns regarding this study apart from a couple of considerations:1)The potential "translational" meaning of the observed findings could be more clearly addressed and detailed.The Reviewer raised an interesting aspect. It is now evident from an overwhelming amount of experimental and animal studies, that oxidative stress has a role in the etiology of hypertension. Unfortunately, data in patients are more varying and still no clear picture of this aspect has been drawn. ...

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Section: Role Of Erk1/2mentioning

confidence: 99%

c-Src, ERK1/2 and Rho kinase mediate hydrogen peroxide-induced vascular contraction in hypertension

García-Redondo

Briones

Martínez-Revelles

et al. 2015

Journal of Hypertension

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“…Reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide (H 2 O 2 ), and hydroxyl radical, are chemically reactive compounds that oxidize proteins, nucleic acids, and lipids . ROS are derived from molecular oxygen and formed as a natural by‐product of aerobic metabolism.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen Peroxide‐Responsive Nanoparticle Reduces Myocardial Ischemia/Reperfusion Injury

Bae

Park

Kang

et al. 2016

JAHA

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BackgroundDuring myocardial ischemia/reperfusion (I/R), a large amount of reactive oxygen species (ROS) is produced. In particular, overproduction of hydrogen peroxide (H2O2) is considered to be a main cause of I/R‐mediated tissue damage. We generated novel H2O2‐responsive antioxidant polymer nanoparticles (PVAX and HPOX) that are able to target the site of ROS overproduction and attenuate the oxidative stress‐associated diseases. In this study, nanoparticles were examined for their therapeutic effect on myocardial I/R injury.Methods and ResultsThe therapeutic effect of nanoparticles during cardiac I/R was evaluated in mice. A single dose of PVAX (3 mg/kg) showed a significant improvement in both cardiac output and fraction shortening compared with poly(lactic‐coglycolic acid) (PLGA) particle, a non‐H2O2‐activatable nanoparticle. PVAX also significantly reduced the myocardial infarction/area compared with PLGA (48.7±4.2 vs 14.5±2.1). In addition, PVAX effectively reduced caspase‐3 activation and TUNEL‐positive cells compared with PLGA. Furthermore, PVAX significantly decreased TNF‐α and MCP‐1 mRNA levels. To explore the antioxidant effect of PVAX by scavenging ROS, dihydroethidium staining was used as an indicator of ROS generation. PVAX effectively suppressed the generation of ROS caused by I/R, whereas a number of dihydroethidium‐positive cells were observed in a group with PLGA I/R. In addition, PVAX significantly reduced the level of NADPH oxidase (NOX) 2 and 4 expression, which favors the reduction in ROS generation after I/R.ConclusionsTaken together, these results suggest that H2O2‐responsive antioxidant PVAX has tremendous potential as a therapeutic agent for myocardial I/R injury.

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“…However, animals that survived the induction of pulmonary thromboembolism through prior treatment with derivative 3a, showed reduction of thrombus size and thrombi deposition after five days, indicating that the mechanism of action of this derivative may ease fibrinolysis and clot removal over time, which may be related to the high survival rate observed for this molecule 41,42 . The lack of inhibition observed for U-44619-induced platelet aggregation suggests that the presence of the compounds does not influence the TP receptor activity, prompting that the inhibition of ARA-induced aggregation relies in the inhibition of upstream enzymes [43][44][45] . The measurements of TXB 2 and PGE 2 plasma levels comprise a usual tool to assess the normal function of COX-1 and TXS in PRP samples [46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Saito

Lourenço

Dias

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE 2 and TXB 2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.

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Signaling pathways involved in the H2O2-induced vasoconstriction of rat coronary arteries

Cited by 33 publications

References 50 publications

c-Src, ERK1/2 and Rho kinase mediate hydrogen peroxide-induced vascular contraction in hypertension

c-Src, ERK1/2 and Rho kinase mediate hydrogen peroxide-induced vascular contraction in hypertension

Hydrogen Peroxide‐Responsive Nanoparticle Reduces Myocardial Ischemia/Reperfusion Injury

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

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