Abstract Body (Do not enter title and authors here): Background: β1 adrenergic receptor (β1-AR) autoantibodies (β1-AA) can cause heart failure (HF) through activating of β1-AR; However, β-AR antagonists cannot completely reverse the cardiac injury induced by β1-AA and improve the survival rate of patients with β1-AA-positive HF. However, the β1-AR-independent mechanisms of heart failure induced by β1-AA are unclear.
Methods: Proteomics of mice hearts was used to identify the specific changed proteins induced by β1-AA. The expression of phosphodiesterase 4B (PDE4B) was detected by western blot in neonatal mice mouse cardiomyocytes (NMCMs) and heart tissues. The binding proteins with β1-AA were enriched by immunoprecipitation (IP) and identified by mass spectrum. The interaction between β1-AA and prostaglandin E2 Receptor EP1 was detected by co-IP and surface plasmon resonance. The cardiac function and cardiac remodeling of PDE4B transgenic (TG) mice and EP1 knockout (KO) mice.
Results: Firstly, PDE4B was changed the most proteins induced by β1-AA compared to β1 adrenergic receptor dobutamine. Moreover, the decrease of PDE4B induced by β1-AA cannot be reversed by metoprolol in vivo and in vitro. Secondly, the cAMP/PKA pathway and cardiac injury/dysfunction induced by β1-AA were inhibited after activation of PDE4B or PDE4B-TG in vivo and in vitro. Thirdly, β1-AA can bind with EP1 and activate Gq/IP3 pathway. The activation effect was abolished by EP1 antagonist. Lastly, blocked EP1 or EP1-KO will reverse the decreased PDE4B and cardiac injury/dysfunction induced by β1-AA.
Conclusions: Our work reveals that β1-AA can activate of EP1/PDE4B pathway to result in heart failure.