Endothelial Dysfunction and Elevated Blood Pressure in
            <i>Mas</i>
            Gene-Deleted Mice

Xu, Ping; Costa‐Goncalves, Andrey C. da; Todiras, Mihail; Rabelo, Luíza Antas; Sampaio, Walkyria Oliveira; Moura, Marina Matos de; Santos, Sergio Sousa; Luft, Friedrich C.; Bäder, Michael; Groß, Volkmar; Alenina, Natalia; Santos, Robson Augusto Souza

doi:10.1161/hypertensionaha.107.102764

Cited by 181 publications

(150 citation statements)

References 46 publications

(37 reference statements)

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“…35 Indeed, we have shown recently that genetic deletion of Mas in FVB/N mice produced a significant increase in blood pressure associated with endothelium dysfunction. 36 An increase of vascular resistance in many organs 37 and a marked endothelium dysfunction 38 was also observed in Mas Ϫ/Ϫ C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 93%

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Savergnini

Beiman²,

Lautner³

et al. 2010

Hypertension

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105

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Abstract-Mas stimulation with angiotensin (Ang)-(1-7) produces cardioprotective effects and vasorelaxation. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate G protein-coupled receptors, we discovered a novel Mas agonist peptide, CGEN-856S. An endothelium-and NO-dependent vasodilating effect was observed for CGEN-856S in thoracic aorta rings of rats (maximal value for the relaxant effect: 39.99Ϯ5.034%), which was similar to that produced by Ang-(1-7) (10 Ϫ10 to 10 Ϫ6 mol/L). In addition, the vasodilator activity of this peptide depended on a functional Mas receptor, because it was abolished in aorta rings of Mas-knockout mice. CGEN-856S appears to bind the Mas receptor at the same binding domain as Ang- (1-7), as suggested by the blocking of its vasorelaxant effect with the Ang-(1-7) analogue D-Ala 7 -Ang-(1-7), and by its competitive inhibition of Ang-(1-7) binding to Mas-transfected cells. The effect of CGEN-856S on reperfusion arrhythmias and cardiac function was studied on ischemia reperfusion of isolated rat hearts. We found that picomolar concentration of CGEN-856S (0.04 nmol/L) had an antiarrhythmogenic effect, as demonstrated by a reduction in the incidence and duration of reperfusion arrhythmias. Furthermore, acute infusion of CGEN-856S produced a shallow dose-dependent decrease in mean arterial pressure of conscious spontaneously hypertensive rats. The maximum change during infusion was observed at the highest dose. Strikingly, blood pressure continued to drop in the postinfusion period. The results presented here indicate that the novel Mas agonist, CGEN-856S, might have a therapeutic value, because it induces vasorelaxing, antihypertensive, and cardioprotective effects. (Hypertension. 2010;56:112-120.)

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Section: Discussionmentioning

confidence: 93%

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Savergnini

Beiman²,

Lautner³

et al. 2010

Hypertension

Self Cite

105

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“…22 Masdeficient mice show increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, leading to endothelial dysfunction and straindependent hyper tension through an increase in ROS abundance. 23 Previously, we and others have shown that chronic Ang(1-7) treatment ameliorates endothelial dysfunction in apoE(−/−) mice on a highfat diet. 24,25 However, the effect of Ang(1-7) on vasoconstrictor response to Ang II is yet unknown.…”

Section: February 2014mentioning

confidence: 95%

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

et al. 2014

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Abstract-Apolipoprotein E-deficient (apoE(−/−)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)(1-7) treatment ameliorates endothelial dysfunction in apoE(−/−) mice. However, the mechanism of Ang(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang(1-7) function, we used apoE(−/−) and wildtype mice fed on Western diet that were treated via osmotic minipumps either with Ang(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(−/−) compared with wildtype mice. This apoE(−/−)specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC 20 ), causing renal vasoconstriction. Here, we provide evidence that chronic Ang(1-7) treatment attenuated the renal pressor response to Ang II in apoE(−/−) mice to wildtype levels. Ang(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogenactivated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogenactivated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(−/−) but not in apoE(−/−) mice treated with Ang(1-7). Moreover, Ang(1-7) treatment had no effect in Mas(−/−)/apoE(−/−) doubleknockout mice confirming the specificity of Ang (1-

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“…MAS receptor signalling has in several cases been shown to antagonize the effects of the AT1R signalling both in vitro and in vivo (5,71,(74)(75)(76).…”

Section: At1/mas Heterodimerizationmentioning

confidence: 99%

Functional interactions between 7TM receptors in the Renin-Angiotensin System—Dimerization or crosstalk?

Lyngsø

Erikstrup

Hansen

2009

Molecular and Cellular Endocrinology

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Abstract:The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt-and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure.The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7 transmembrane (7TM) receptors (or G-protein-coupled receptors) such as the angiotensin II Receptors type I and II (AT1R and AT2R) and the MAS-oncogene receptor. Several findings indicate that the 7TM receptors can form both homo-and heterodimers, or higher orders of oligomers. Furthermore, dimerization may be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very difficult to establish if our observations reflect actual well defined dimerization or merely reflect close proximity between the receptors and/or various types of functional interaction. In this review, we will present and critically discuss the current data on 7TM receptor dimerization with a clear focus on the RAS, and delineate future challenges within the field.

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Endothelial Dysfunction and Elevated Blood Pressure in Mas Gene-Deleted Mice

Cited by 181 publications

References 46 publications

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

Functional interactions between 7TM receptors in the Renin-Angiotensin System—Dimerization or crosstalk?

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