Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts. (14th October 2021)

• Record Type: Journal Article
• Authors: Sorrentino, A; Bagwan, N; Linscheid, N; Poulsen, P; Kahnert, K; Thomsen, M; Delmar, M; Lundby, A
• Is Part Of: European heart journal. Volume 42(2021)Supplement 1
• Publication Date: 2021-10-14
• Subjects: Heart Failure; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehab724.3294
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background: The molecular underpinnings of heart failure with reduced ejection fraction (HFrEF) involves a complex remodeling of the contractile, metabolic and electrical functions. Current pharmacotherapy for patients presenting HFrEF includes combination of angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers). Yet, a knowledge gap exists regarding the molecular changes accompanying such treatment. Purpose: The present study takes an omics approach to study protein and phosphorylation signaling derangement in HFrEF and to define the global changes resulting from treatment with β-AR blocker (metoprolol) and ACE inhibitor (enalapril) in control- and HFrEF hearts. Methods and results: For induction of HFrEF, a tight and permanent ligature was applied to constrict the transverse aorta in male C57BL6 mice. Eight weeks post-surgery, an osmotic pump was implanted delivering either vehicle or treatment (enalapril, ACE inhibitor, and metoprolol, β-AR blocker) for a two week period. The proteome- and phosphoproteome of left ventricular tissue was resolved using high-resolution liquid chromatography-mass spectrometry. The resulting dataset covered 6, 004 proteins and 14, 967 phosphorylation events. 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, including a reversal of Pdhk4 activity. In controls, treatment mainly led to downregulation of canonical PKA signaling. Overall, the signaling response elicited by treatment was profoundly different for failing than for control hearts. Conclusions: We used state-of-the-art proteomics and phosphoproteomics approaches to analyze changes in protein abundance and phosphorylation state of the left ventricle resulting from combination therapy with a β-AR blocker and an ACE inhibitor in failing and non-failing hearts. Our observation of divergent signaling outcomes depending on the disease state of the heart underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart. Funding Acknowledgement: Type of funding sources: Foundation. Main funding source(s): The Danish Council for independent ResearchLundbeck FoundationFondation Leducq Transatlantic Network of Excellence