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Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice

  • Molecular and cellular mechanisms of disease
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.

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Acknowledgements

We thank Blanka Duvnjak and Christina Schwandt for their excellent technical assistance.

Funding

This work was supported by DFG (IRTG 1902) to G. Yang, M. Yakoub, J. Stegbauer, L.C. Rump, and M. Grandoch.

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Authors and Affiliations

  1. Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Guang Yang, Sascha Höges, Mina Yakoub, Lydia Hering, Lars Christian Rump & Johannes Stegbauer

  2. Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Geoffrey Istas & Ana Rodriguez-Mateos

  3. Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, Franklin Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK

    Geoffrey Istas & Ana Rodriguez-Mateos

  4. Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, Medical Faculty, University Hospital Essen, Essen, Germany

    Ulrike Hendgen-Cotta & Tienush Rassaf

  5. Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Maria Grandoch

  6. Department of Pharmacology and Toxicology, Ruhr-University Bochum, Bochum, Germany

    Evanthia Mergia

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  1. Guang Yang
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Corresponding author

Correspondence to Johannes Stegbauer.

Ethics declarations

All animal experimental investigations were in accordance with the federal state authority (Landesamt fuer Natur-, Umwelt- und Verbraucherschutz Nordrhein Westfalen; reference: AZ. 8.87-50.10.34.08.216 and AZ 84–02.04.2012.A250) and performed according to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes.

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The authors declare that they have no conflict of interest.

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Yang, G., Istas, G., Höges, S. et al. Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice. Pflugers Arch - Eur J Physiol 470, 661–667 (2018). https://doi.org/10.1007/s00424-018-2108-1

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  • DOI: https://doi.org/10.1007/s00424-018-2108-1

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