Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, German Center for Cardiovascular Research (DZHK) partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom
Claire Poulet
Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom
Jose L Sanchez Alonso Mardones
Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom
Catherine Mansfield
Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom
Andreas Friebe
Physiologisches Institut, University of Würzburg, Würzburg, Germany
Sian E Harding
Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom
Jean-Luc Balligand
Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, German Center for Cardiovascular Research (DZHK) partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
Cardiomyocyte β3-adrenoceptors (β3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3’,5’-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of β3-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β3-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
