cAMP Imaging at Ryanodine Receptors Reveals β2-Adrenoceptor Driven Arrhythmias

Author:

Berisha Filip1,Götz Konrad2,Wegener Jörg W3ORCID,Brandenburg Sören4ORCID,Subramanian Hariharan5,Molina Cristina E1,Rueffer Andre6,Petersen Johannes7ORCID,Bernhardt Alexander8ORCID,Girdauskas Evaldas9,Jungen Christiane10,Pape Ulrike11ORCID,Kraft Axel E1,Warnke Svenja11ORCID,Lindner Diana12ORCID,Westermann Dirk13ORCID,Blankenberg Stefan14,Meyer Christian15ORCID,Hasenfuß Gerd16ORCID,Lehnart Stephan E17ORCID,Nikolaev Viacheslav O1ORCID

Affiliation:

1. Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, GERMANY

2. Cardiology and Pulmonology, University of Goettingen Medical Center, GERMANY

3. Cardiology and Pneumology, University of Goettingen Medical Center, GERMANY

4. Clinic of Cardiology and Pneumology, University Medical Center Goettingen, GERMANY

5. Institute of Experimental Cardiovascular Research, University Medical Center Hamburg- Eppendorf, GERMANY

6. Cardiovascular Surgery, University Hospital Erlangen, GERMANY

7. Cardiovascular Surgery, University Heart and Vascular Center Hamburg, GERMANY

8. Cardiovascular Surgery, University Heart Center Hamburg, GERMANY

9. Cardiovascular Surgery, University Heart Center Hamburg

10. Cardiology, University Heart Center, University Hospital Hamburg-Eppendorf, GERMANY

11. Cardiology, University Heart Center Hamburg, GERMANY

12. Clinic for General and interventional Cardiology, University Heart Center Hamburg, GERMANY

13. Cardiology, UKE Hamburg, GERMANY

14. General and interventional Cardiology, University Heart Center Hamburg, GERMANY

15. EVK Düsseldorf

16. University of Göttingen Medical Center

17. Cardiology and Pulmonology, University Medical Center Goettingen, GERMANY

Abstract

Rationale: 3',5'-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which, upon β-adrenergic receptor (β-AR) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac ryanodine receptor type 2 (RyR2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum (SR) often occurring in heart failure. Objective: We sought to establish a real time live cell imaging approach capable of directly visualizing cAMP in the vicinity of mouse and human RyR2 and to analyze its pathological changes in failing cardiomyocytes under β-AR stimulation. Methods and Results: We generated a novel targeted fluorescent biosensor Epac1-JNC for RyR2-associated cAMP and expressed it in transgenic mouse hearts as well in human ventricular myocytes using adenoviral gene transfer. In healthy cardiomyocytes, β 1 -AR but not β 2 -AR stimulation strongly increased local RyR2-associated cAMP levels. However, already in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of phosphodiesterases (PDEs) 2, 3 and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurableβ2-AR/AMP signals in the vicinity of RyR2 in failing mouse and human myocytes, increased β2-AR-dependent RyR2 phosphorylation, SR calcium leak and arrhythmia susceptibility. Conclusions: Our new imaging approach could visualize cAMP levels in the direct vicinity of cardiac RyR2. Unexpectedly, in mouse and human failing myocytes, it could uncover functionally relevant local arrhythmogenic β2-AR/cAMP signals which might be an interesting antiarrhythmic target for heart failure.

Funder

Deutsche Forschungsgemeinschaft

Deutsches Zentrum für Herz-Kreislaufforschung

Gertraud und Heinz-Rose Stiftung

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

Reference178 articles.

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4. approaches for heart failure;Circulation.,2010

5. .1161/CIRCULATIONAHA.109.890954

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