Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts
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Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and β-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of β-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of β-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.
|Status||Udgivet - dec. 2022|
The authors thank all lab members for fruitful discussion, the mass spectrometry platform for excellent technical assistance, Amer Mujezinovic for excellent assistance in all animal experiments, and Nancy Mutsaers for graphical assistance. The mass spectrometry measurements were performed at The Novo Nordisk Foundation Center for Protein Research, which is funded in part by a generous donation from the Novo Nordisk Foundation (NNF14CC0001). The project was mainly supported by The Danish Council for independent Research by grant DFF-4092-00045 to A.L. as well as a post doctoral fellowship from the Lundbeck Foundation (R322-2019-2698) to A.S. and a Fondation Leducq Transatlantic Network of Excellence (M.D., A.L).
© 2022, The Author(s).