SERCA2a microdomain cAMP changes in heart failure with preserved ejection fraction

This editorial refers to ‘Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes’, by P. Lai et al., https://doi.org/10.1093/cvr/cvad178. While heart failure with preserved ejection fraction (HFpEF) may soon become the leading form of heart failure, existing therapeutic interventions target mainly heart failure with reduced ejection fraction (HFrEF). HFpEF is characterized by diverse aetiologies and complex phenotypes, with obesity and type 2 diabetes (T2D) being major contributing factors.1–3 Both the diverse risk factors and pathomechanisms warrant novel, targeted therapies to treat HFpEF. Therefore, improved understanding of the pathophysiology of HFpEF particularly in the context of the leading risk factors obesity and T2D is increasingly important. In this issue, Lai et al. explore the cyclic nucleotide dynamics in cardiomyocytes, focusing on the SERCA2a (Sarco/Endoplasmic Reticulum Ca2+-ATPase type 2a)-regulated intracellular calcium dynamics in the context of HFpEF.4 To investigate cyclic nucleotide dynamics in this adult cardiomyocyte microdomain, regulating the sarcoendoplasmic reticulum (SER) Ca2+ uptake-pump SERCA2a, a major determinant of myocardial relaxation, Lai et al. developed a new double transgenic mouse model with both alleles harbouring the peprdb leptin mutation (db/db)4 in combination with stable overexpression of the Epac1-PLN (fusion protein with phospholamban) Förster resonance energy transfer biosensor (Figure 1).5,6 On the one hand, db/db mice developed obesity, T2D, and HFpEF with mild left-ventricular hypertrophy and elevated left-atrial filling pressures.3,7 On the other hand, Epac1 detected changes in intracellular 3′,5′-cyclic adenosine monophosphate (cAMP), a crucial second messenger in cellular signalling, specifically in the SERCA2a microdomain, where PLN (phospholamban), a 52-aa protein tail-anchored in the SR membrane binds to and inhibits SERCA2a activity under resting conditions.5 Under physiological conditions, transient β-adrenoceptor (β-AR) stimulation by catecholamines would acutely increase PLN phosphorylation, resulting in release of its inhibitory SERCA2a effect, increased SR Ca2+ uptake, and both faster decay of intracellular Ca2+ transients and myocardial relaxation (Figure 1). Upper left: isolated mouse ventricular cardiomyocyte from a db/db::Epac1-PLN transgenic heart. Apparently, the EPAC1 signal shows primarily a striated pattern, but also a less prominent longitudinal distribution indicating correct distribution in the SER membrane network near the Z-lines and along the myofibrils. Upper right: the transgenic EPAC1-PLN biosensor detects intracellular cAMP changes, e.g. a cAMP increase leads to a decrease in CFP-to-YFP Förster energy transfer (indicated each by the length of the cyan and yellow light waves before and after cAMP binding, respectively), decreasing the fluorescent YFP (yellow fluorescent protein) signal. Lower red box: in db/db::EPAC1-PLN cardiomyocytes, β1-AR induced cAMP generation and subsequent PLN phosphorylation are desensitized; meanwhile β2-AR signalling is enhanced, due to each a loss of PDE4 functional coupling with the β2-AR and association with PLN, leading to a sustained increase of cAMP in the PLN/SERCA2a microdomain. Courtesy of and with permission by Dr. V.O. Nikolaev.4 Live imaging of db/db but not of healthy control (db/+) cardiomyocytes showed that the β2-AR subtype generated a chronic cAMP increase in the PLN/SERCA2a microdomain, which was accompanied by increased PLN (hyper-)phosphorylation, accelerated SR Ca2+ uptake, and increased contractile relaxation (lusitropy). In contrast, db/db cardiomyocytes revealed a desensitization of β1-AR stimulated cAMP pools in the PLN/SERCA2a microdomain, which is expected to contribute to a blunted lusitropic effect. Together, these findings suggest that a compensatory mechanism based predominantly on β2-AR stimulation of cAMP synthesis to maintain and sustain PLN/SERCA2a dependent SR Ca2+ uptake and cardiac relaxation. A mechanism that degrades cAMP specifically in the PLN/SERCA2a protein complex, where SERCA2a may exist in dimers or higher order oligomers together with additional proteins, are phosphodiesterase 4 (PDE4) isoforms. Interestingly, a local loss of cAMP degrading PDE4D associated specifically with the PLN/SERCA2a complex can explain the increased cAMP levels following β2-AR stimulation in db/db cardiomyocytes isolated from HFpEF hearts. A PDE4D decrease has been reported in HFrEF previously, contributing to Ryanodine Receptor type 2 (RyR2) SER Ca2+ release channel hyper-phosphorylation.8 In this context, one major difference compared to HFpEF appears to be a decrease or PLN hypo-phosphorylation in HFrEF, a mechanism known to inhibit SER Ca2+ uptake and to promote cytosolic Ca2+ overload. In cardiomyocytes, increases in cAMP activate cAMP-dependent protein kinases and exchange protein directly activated by cAMP (Epac), which modulate cytosolic Ca2+ influx and SER Ca2+ uptake by activating L-type Ca2+ channels (LTCCs), RyR2 channels, and SERCA2a.9,10 These proteins are thought to be regulated by different β2-AR subtypes, protein kinases tethered to specific A-kinase anchoring proteins (AKAPs) and cAMP degrading PDE enzymes in distinct subcellular microdomains. However, our understanding of these dynamic cAMP regulatory mechanisms in HFpEF with obesity and T2D is very limited as compared to HFrEF. Notably, Lai et al. present the first comprehensive study that resolves cAMP dynamics in the functionally highly relevant PLN/SERCA2a microdomain in a novel murine HFpEF model.4 Transitioning from animal models to human studies is crucial towards validating these HFpEF mechanisms. Towards translating these findings into novel therapeutic approaches deeper elucidation of the molecular pathway and identification of druggable targets is needed, alongside longitudinal studies to understand the progression of HFpEF in the context of obesity and T2D. Integrating multiomics approaches could help uncover novel biomarkers and targets, steering towards personalized medicine based on individual genetic and metabolic profiles. Towards this end, the study of Lai et al. not only advances our understanding of HFpEF pathophysiology but also opens avenues for targeted therapeutic interventions, especially in patients with obesity and T2D.4 M.G. has been supported by DZHK (German Centre for Cardiovascular Research) partner site Berlin, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. S.E.L. has been supported by the Collaborative Research Center SFB1002 ‘Modulatory Units in Heart Failure’, University of Göttingen, Göttingen, Germany; by the Collaborative Research Center SFB1190 ‘Compartmental Gates and Contact Sites in Cells’, University of Göttingen, Göttingen, Germany; by the Cluster of Excellence ‘Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells’ (MBExC2067), Göttingen, Germany; and by DZHK (German Centre for Cardiovascular Research) partner site Göttingen, Göttingen, Germany. No new data were generated or analysed in support of this research.