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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1967.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Caffeine Enhances Endothelial Repair by an AMPK-Dependent Mechanism

Ioakim Spyridopoulos; Stephan Fichtlscherer; Rüdiger Popp; Stefan W. Toennes; Beate Fisslthaler; Thomas Trepels; Alma Zernecke; Elisa A. Liehn; Christian Weber; Andreas M. Zeiher; Stefanie Dimmeler; Judith Haendeler

From Molecular Cardiology, Department of Internal Medicine III (I.M., I.S., S.F., T.T., A.M.Z., S.D., J.H.), University of Frankfurt, Germany; the Department of Physiology (R.P., B.F.), University of Frankfurt, Germany; the Department of Forensic Toxicology (S.W.T.), University of Frankfurt, Germany; the Institute for Molecular Cardiovascular Research (IMCAR) (A.Z., E.A.L., C.W.), RWTH Aachen University, Germany. Current affiliation for J.H.: Molecular Cell & Aging Research, Institut fuer umweltmedizinische Forschung (IUF), University of Duesseldorf GmbH, Germany.

Correspondence to Judith Haendeler, PhD, Molecular Cell & Aging Research, Institut fuer Umweltmedizinische Forschung, University of Duesseldorf GmbH, Auf‘m Hennekamp 50, 40225 Duesseldorf, Germany. E-mail juhae001{at}uni-duesseldorf.de and Ioakim Spyridopoulos, Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, 60590 Frankfurt, Germany. E-mail: spyridopoulos@uni-frankfurt.de.

Objective— Migratory capacity of endothelial progenitor cells (EPCs) and mature endothelial cells (ECs) is a key prerequisite for endothelial repair after denuding injury or endothelial damage.

Methods and Results— We demonstrate that caffeine in physiologically relevant concentrations (50 to 100 µmol/L) induces migration of human EPCs as well as mature ECs. In patients with coronary artery disease (CAD), caffeinated coffee increased caffeine serum concentration from 2 µmol/L to 23 µmol/L, coinciding with a significant increase in migratory activity of patient-derived EPCs. Decaffeinated coffee neither affected caffeine serum levels nor migratory capacity of EPCs. Treatment with caffeine for 7 to 10 days in a mouse-model improved endothelial repair after denudation of the carotid artery. The enhancement of reendothelialization by caffeine was significantly reduced in AMPK knockout mice compared to wild-type animals. Transplantation of wild-type and AMPK^–/– bone marrow into wild-type mice revealed no difference in caffeine challenged reendothelialization. ECs which were depleted of mitochondrial DNA did not migrate when challenged with caffeine, suggesting a potential role for mitochondria in caffeine-dependent migration.

Conclusion— These results provide evidence that caffeine enhances endothelial cell migration and reendothelialization in part through an AMPK-dependent mechanism, suggesting a beneficial role for caffeine in endothelial repair.

We demonstrate that caffeine in physiologically relevant concentrations (50 to 100 µmol/L) induces migration of human endothelial progenitor cells as well as mature endothelial cells. The enhancement of reendothelialization by caffeine in a mouse-model after denudation of the carotid artery was significantly reduced in AMPK knockout mice compared to wild-type animals.

Key Words: caffeine • reendothelialization • endothelium • AMPK • mitochondria

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