Abstract
Failure to reperfuse the coronary microvasculature (“no-reflow”) affects up to 50% of patients after unblocking a coronary artery that was causing ischaemia and acute myocardial infarction. This “no-reflow” is associated with reduced left ventricular ejection fraction, increased infarct size and death. We show that the incretin hormone GLP-1 (glucagon-like peptide 1) can be used to protect the heart after ischaemia by activating ATP-sensitive K+ channels on pericytes that constrict coronary capillaries. Coronary capillary dilation can be activated pharmacologically or by vagally-mediated GLP-1 release from the gut evoked by skeletal muscle ischaemia, and is abolished by block or genetic deletion of pericyte KATP channels. These results define a brain-gut-heart pathway mediating cardioprotection and suggest pharmacological therapies to reduce ischaemia-induced coronary no-reflow and improve post-infarct recovery.
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The data that support the findings of this study are available within the article or from the corresponding author upon request. The source data underlying Figs. 2–4 are provided as a Source data file. Source data are provided with this paper.
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Acknowledgements
The study was supported by the British Heart Foundation Intermediate Basic Science Research Fellowship (FS/IBSRF/21/25060) to S.M., and an ERC Advanced Investigator Award (740427, BrainEnergy), Wellcome Trust Senior Investigator Award (099222/Z/12/Z), a Rosetrees Trust grant (M153-F2), and a BHF/UK-DRI Centre for Vascular Dementia Research grant to D.A. The authors thank Frank Kirchhoff for NG2-Cre mice, Akiko Nishiyama and Dirk Dietrich for NG2-dsRed mice, Andrew Tinker for Kir6.1flx/flx mice, Elisa Avolio for providing human pericyte culture, David Hodson and Johannes Broichhagen for providing Luxendin555 probe, Thomas Kampourakis for suggesting the use of Mavacamten, Stuart Martin for genotyping, and Wolfgang Langhans, Alice Adriaenssens and Sergey Kandabarau for advice during this work.
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S.M. and D.A. designed experiments. S.M. performed experiments and analysed the data. F.S.S.F. performed immunostaining for the study of perfusion volume and capillary blockages (Fig. 2), L.E.E. performed experiments and immunostaining for the Kir6.1 localisation study (Fig. 4d, e). S.M. and D.A. wrote the manuscript.
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Mastitskaya, S., de Freitas, F.S.S., Evans, L.E. et al. GLP-1 activates KATP channels in coronary pericytes as the effector of brain-gut-heart signalling mediating cardioprotection. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69555-1
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DOI: https://doi.org/10.1038/s41467-026-69555-1
