Selective changes in cytosolic β-adrenergic cAMP signals and L-type Calcium Channel regulation by Phosphodiesterases during cardiac hypertrophy. (January 2021)

• Record Type: Journal Article
• Authors: Abi-Gerges, Aniella; Castro, Liliana; Leroy, Jérôme; Domergue, Valérie; Fischmeister, Rodolphe; Vandecasteele, Grégoire
• Is Part Of: Journal of molecular and cellular cardiology. Volume 150(2021)
• Page Start: 109
• Page End: 121
• Publication Date: 2021-01
• Subjects: Cardiac hypertrophy - cyclic nucleotide phosphodiesterases -- cAMP - L-type Ca2+ current; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.10.011
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background In cardiomyocytes, phosphodiesterases (PDEs) type 3 and 4 are the predominant enzymes that degrade cAMP generated by β-adrenergic receptors (β-ARs), impacting notably the regulation of the L-type Ca 2+ current ( I Ca, L ). Cardiac hypertrophy (CH) is accompanied by a reduction in PDE3 and PDE4, however, whether this affects the dynamic regulation of cytosolic cAMP and I Ca, L is not known. Methods and Results CH was induced in rats by thoracic aortic banding over a time period of five weeks and was confirmed by anatomical measurements. Left ventricular myocytes (LVMs) were isolated from CH and sham-operated (SHAM) rats and transduced with an adenovirus encoding a Förster resonance energy transfer (FRET)-based cAMP biosensor or subjected to the whole-cell configuration of the patch-clamp technique to measure I Ca, L . Aortic stenosis resulted in a 46% increase in heart weight to body weight ratio in CH compared to SHAM. In SHAM and CH LVMs, a short isoprenaline stimulation (Iso, 100 nM, 15 s) elicited a similar transient increase in cAMP with a half decay time (t1/2off ) of ~50 s. In both groups, PDE4 inhibition with Ro 20-1724 (10 μM) markedly potentiated the amplitude and slowed the decline of the cAMP transient, this latter effect being more pronounced in SHAM (t1/2off ~ 250 s) than in CH (t1/2off ~ 150 s, P < 0.01). In contrast, PDE3 inhibition with cilostamide (1 μM) had no effect on the amplitude of the cAMP transient and a minimal effect on its recovery in SHAM, whereas it potentiated the amplitude and slowed the decay in CH (t1/2off ~ 80 s). Iso pulse stimulation also elicited a similar transient increase in I Ca, L in SHAM and CH, although the duration of the rising phase was delayed in CH. Inhibition of PDE3 or PDE4 potentiated I Ca, L amplitude in SHAM but not in CH. Besides, while only PDE4 inhibition slowed down the decline of I Ca, L in SHAM, both PDE3 and PDE4 contributed in CH. Conclusion These results identify selective alterations in cytosolic cAMP and I Ca, L regulation by PDE3 and PDE4 in CH, and show that the balance between PDE3 and PDE4 for the regulation of β-AR responses is shifted toward PDE3 during CH. Graphical abstract: Unlabelled Image Highlights: PDE4 shapes cytosolic β-adrenergic cAMP signals in normal rat cardiomyocytes PDE4 and PDE3 shape cytosolic β-adrenergic cAMP signals in hypertrophied myocytes Potentiation of ICa, L by PDE3 and PDE4 is impaired in hypertrophied myocytes PDE3 contributes to ICa, L recovery from β-adrenergic stimulation in hypertrophy PDE control of β-adrenergic stimulation is shifted toward PDE3 in hypertrophy