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Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction

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Abstract

Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress. However, the underlying mechanisms are incompletely understood and may involve endothelial NOX-2 upregulation or facilitated vascular infiltration of phagocytic cells. Therefore, the current study was designed to investigate the vascular effects of chronic angiotensin II (AngII) infusion in mice with an endothelial-specific α1AMPK deletion. A mouse strain with endothelial-specific α1AMPK deletion was generated by breeding α1AMPKflox/flox mice with TekCre+ or Cadh5Cre+ mice. Chronic AngII infusion (0.5 mg/kg/day for 7day) caused mild endothelial dysfunction in wild-type mice that was significantly aggravated in endothelial α1AMPK knockout mice. Aortic NOX-2 and CD68 expression were increased, indicating that infiltrating leukocytes may significantly contribute to enhanced vascular oxidative stress. Flow cytometry revealed a higher abundance of aortic CD90.2+ T-cells, CD11b+F4/80+ macrophages and Ly6G−Ly6C+ monocytes. Vascular mRNA expression of monocyte chemoattractant protein 1, CCL5 and vascular cell adhesion molecule 1 was enhanced in AngII-infused mice lacking endothelial α1AMPK, facilitating the recruitment of inflammatory cells to the vessel wall. In addition, AngII-induced upregulation of cytoprotective heme oxygenase 1 (HO-1) was blunted in mice with endothelial α1AMPK deletion, compatible with an impaired antioxidant defense in these animals. In summary, endothelial expressed α1AMPK limits the recruitment of inflammatory cells to the vessel wall and maintains HO-1 mediated antioxidant defense. Both mechanisms reduce vascular oxidative damage and preserve endothelial function during chronic AngII treatment.

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Abbreviations

ACh:

Acetylcholine

AMP:

Adenosine monophosphate

AMPK:

AMP-activated protein kinase

AngII:

Angiotensin II

CCR2:

C–C chemokine receptor type 2

CCL5:

CC-chemokine ligand 5

DHE:

Dihydroethidium

eNOS:

Endothelial nitric oxide synthase

GTN:

Glycerol trinitrate

HO-1:

Heme oxygenase 1

NADPH:

Nicotinamide adenine dinucleotide phosphate, reduced form

MCP-1:

Monocyte chemotactic protein 1

NO:

Nitric oxide

ROS:

Reactive oxygen species

PEG-SOD:

Polyethylene-glycolated-superoxide dismutase

TBP:

TATA box binding protein

VCAM-1:

Vascular cell adhesion protein 1

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Acknowledgements

We thank Bettina Mros, Angelica Karpi, Jessica Rudolph and Jörg Schreiner for excellent technical assistance. Data of the present study are part of the medical thesis of Thi Lan P. Tran. This work was supported by the European Commission integrated project (LSHM-CT-2004-005272/exgenesis) to B.V., by the German Research Foundation (DFG SCHU 1486/4-1 to E.S. and DFG WE4361/7-1 to P.W.) and by the Federal Ministry of Education and Research (BMBF 01EO1503).

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Author notes

  1. Swenja Kröller-Schön and Thomas Jansen contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology 1, Center for Cardiology, Universitätsmedizin Mainz, 55131, Mainz, Germany

    Swenja Kröller-Schön, Thomas Jansen, Thi Lan P. Tran, Miroslawa Kvandová, Sanela Kalinovic, Matthias Oelze, Andreas Daiber, Katie Frenis, Philip Wenzel, Thomas Münzel & Eberhard Schulz

  2. Center for Thrombosis and Hemostasis (CTH), Universitätsmedizin Mainz, 55131, Mainz, Germany

    Sabine Kossmann, Jeremy Lagrange & Philip Wenzel

  3. Inserm, U1016, Institut Cochin, Paris, France

    Marc Foretz & Benoit Viollet

  4. Cnrs, UMR8104, Paris, France

    Marc Foretz & Benoit Viollet

  5. Univ Paris Descartes, Paris, France

    Marc Foretz & Benoit Viollet

  6. Division of Cardiovascular Medicine, UMass Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA

    John F. Keaney Jr.

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  1. Swenja Kröller-Schön
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  2. Thomas Jansen
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Kröller-Schön, S., Jansen, T., Tran, T.L.P. et al. Endothelial α1AMPK modulates angiotensin II-mediated vascular inflammation and dysfunction. Basic Res Cardiol 114, 8 (2019). https://doi.org/10.1007/s00395-019-0717-2

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