EN
Specific targeting of β1-adrenoceptor/cAMP microdomains to treat HFpEF (RP1)
Principal Investigators
Project Summary and Goals
cAMP as a prototypic second messenger has provided a paradigm for compartmentalized, microdomain-specific subcellular signaling. In cardiomyocytes, this can generate distinct functional outcomes, e.g. improve contractility/relaxation and promote cardiac remodeling downstream of the same β1-adrenoceptor (β1-AR). Current heart failure (HF) therapies, such as β-blockers, target both mechanisms and, while providing valuable antihypertrophic effects, they diminish cardiac contractility and relaxation, which is undesirable for HFrEF and HFpEF patients, respectively. Based on recent evidence from our laboratories, we have developed a new class of β-blockers acting preferentially at cardiomyocyte outer membrane which leads to ameliorated nuclear cAMP activity and attenuated cardiac remodeling. In contrast, these drugs do not inhibit β1-AR in the so-called T-tubuli and at intracellular membranes, which are known to regulate L-type Ca2+ channel current and phospholamban phosphorylation responsible for cardiomyocyte contractility and relaxation, respectively.
Aims Addressed by the Doctoral Candidates
- Study therapeutic potential of new antibody-based β-blocker in vivo using two mouse models of HFpEF in terms of diastolic function and cardiac remodeling.
- Evaluate microdomain-specific molecular mechanisms of β-blocker effects in isolated healthy and HFpEF mouse and human myocytes by cutting-edge live cell imaging, functional and biochemical assays.
Key Techniques
- Cardiomyocytes isolation
- Förster resonance energy transfer (FRET) biosensors
- Scanning Ion Conductance Microscopy (SICM)
- Ion channel recordings
- Cardiomyocyte contractility and calcium transient measurements (CytoCypher)
- Animal models of heart failure
Publications
-
Distinct functions of cardiac β-adrenergic receptors in the T-tubule vs. outer surface membrane. Maders GWP, Barthé M, Lefebvre F, Langlois E, F Lefebvre F, Lechêne P, Iturrioz X, Ha-Duong T, Moine L, Llorens-Cortes C, Ha-Duong T, Tsapis N, Fischmeister R (2025). Elife. 14:e84243. -
Gene therapy with phosphodiesterases 2A and 4B ameliorates heart failure and arrhythmias by improving subcellular cAMP compartmentation . Pavlaki N, Froese A, Li W, De Jong KA, Geertz B, Subramanian H, Mohagaonkar S, Luo X, Schubert M, Wiegmann R, Margaria JP, Ghigo A, Kämmerer S, Hirsch E, El-Armouche A, Guan K, Nikolaev VO (2024). Cardiovasc Res. 120:1011-1023. -
Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes. Lai P, Hille SS, Subramanian H, Wiegmann R, Roser P, Müller OJ, Nikolaev VO, De Jong KA (2024). Cardiovasc Res. 120:273-285. -
cAMP Imaging at ryanodine receptors reveals β2-adrenoceptor driven arrhythmias . Berisha F, Götz K, Wegener JW, Brandenburg S, Subramanian H, Molina CE, Rueffer A, Petersen J, Bernhardt A, Girdauskas E, Jungen C, Pape U, Kraft AE, Warnke S, Lindner D, Westermann D, Blankenberg S, Meyer C, Hasenfuß G, Lehnart SE, Nikolaev VO (2021). Circ Res. 129:81-94. -
Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation . Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J (2010). Science. 327:1653-1657.