ArticleCardiovascular research2024
Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes.
Article in Cardiovascular research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 14 citations in OpenAlex.
- Review
- Global and Regional Voltage and Calcium-Transient Responses to Acute Cardiac Contractility Modulation in Isoproterenol-Treated Rat Hearts with Features Compatible with Early Remodeling.Life (Basel, Switzerland) · 2026Article
- The functional role of the circular RNA circCDR1as targeting SERCA2a in the progression of pathological cardiac hypertrophy and heart failure.Journal of translational medicine · 2026Article
- Mechanobiology of the diabetic cardiomyocyte: insulin signaling, titin elasticity, and multiscale mechanical dysfunction.Biophysical reviews · 2026Review
- RHOT Proteins Link Mitochondrial Motility to Cardiomyocyte Sarcomere Maturation.Circulation research · 2026Article
- Phosphodiesterase 8 regulation of excitation-contraction coupling as a target for cardiovascular disease: is it my turn now?American journal of physiology. Heart and circulatory physiology · 2026Review
- Sex-specific cardioprotective role of miR-30a-5p through estrogen-dependent mechanisms in a mouse model of heart failure.Cardiovascular diabetology · 2026Article
- Calcium dysregulation in diabetic cardiomyopathy & heart failure with preserved ejection fraction.Frontiers in cardiovascular medicine · 2026Review
- The Potential Connection Between Mechanical Stress and Heart Failure with Preserved Ejection Fraction: Mechanistic Insights and Therapeutic Potential.International journal of medical sciences · 2026Review
- The SERCA-PLN-DWORF axis in cardiometabolic disease: mechanisms and therapeutic perspectives.Cardiovascular diabetology · 2025Review
- Autonomic imbalance in cardiovascular disease: molecular mechanisms and emerging therapeutics.American journal of physiology. Cell physiology · 2025Review
- SERCA2a dysfunction in the pathophysiology of heart failure with preserved ejection fraction: a direct role is yet to be established.Heart failure reviews · 2025Review
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy.British journal of pharmacology · 2025Article
- Review
- Harnessing RNA therapeutics: novel approaches and emerging strategies for cardiovascular disease management.Frontiers in cardiovascular medicine · 2025Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
aimsDespite massive efforts, we remain far behind in our attempts to identify effective therapies to treat heart failure with preserved ejection fraction (HFpEF). Diastolic function is critically regulated by sarcoplasmic/endoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a), which forms a functional cardiomyocyte (CM) microdomain where 3',5'-cyclic adenosine monophosphate (cAMP) produced upon β-adrenergic receptor (β-AR) stimulation leads to phospholamban (PLN) phosphorylation and facilitated Ca2+ re-uptake. METHODS AND
resultsTo visualize real-time cAMP dynamics in the direct vicinity of SERCA2a in healthy and diseased myocytes, we generated a novel mouse model on the leprdb background that stably expresses the Epac1-PLN Förster resonance energy transfer biosensor. Mice homozygous for the leprdb mutation (db/db) developed obesity and type 2 diabetes and presented with a HFpEF phenotype, evident by mild left ventricular hypertrophy and elevated left atria filling pressures. Live cell imaging uncovered a substantial β2-AR subtype stimulated cAMP response within the PLN/SERCA2a microdomain of db/db but not healthy control (db/+) CMs, which was accompanied by increased PLN phosphorylation and accelerated calcium re-uptake. Importantly, db/db CMs also exhibited a desensitization of β1-AR stimulated cAMP pools within the PLN/SERCA2a microdomain, which was accompanied by a blunted lusitropic effect, suggesting that the increased β2-AR control is an intrinsic compensatory mechanism to maintain PLN/SERCA2a-mediated calcium dynamics and cardiac relaxation. Mechanistically, this was due to a local loss of cAMP-degrading phosphodiesterase 4 associated specifically with the PLN/SERCA2a complex.
conclusionThese newly identified alterations of cAMP dynamics at the subcellular level in HFpEF should provide mechanistic understanding of microdomain remodelling and pave the way towards new therapies.
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