Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts

Abstract

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.

Multi‐omic analyses and network biology in cardiovascular disease

“…Alongside these patient data, phosphoproteomic analyses from preclinical experimental models provide additional insights into protein phosphorylation dynamics in heart disease. MS-based phosphoproteome profiling has been performed in mouse models of HFpEF [91], HFrEF (by transverse aortic constriction) [92] including with and without treatment with angiotensin-converting enzyme inhibitor and β-receptor blocker therapy [93], and in genetic models of phospholamban R9C DCM [94]. Moreover, given its indispensable role in mediating cardiac contraction and relaxation, phosphoproteomic analysis of the myofilament subproteome in a clinically relevant swine acute MI model revealed downregulated phosphorylation levels of several myofilament and Z-disc proteins post-MI [95].…”

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial

“…9 HF disease-modifying drugs exert pleiotropic effects, including an associated change in proteomics that additionally helps further our understanding of the mechanisms behind the prognostic benefits of treatment. 10,11,12,13 In this post hoc analysis of the Heart 'OMics' in AGEing (HOMAGE) trial, we investigated differences in the clinical characteristics, plasma proteins, and collagen metabolism among participants classified by the presence or absence of CAD and MI.…”

“…Patients with HF exhibit unique proteomic profiles, reflecting differences between ischaemic‐ and non‐ischaemic pathophysiological pathways, 5,6 and further helping risk stratification 7,8 and the development of new therapeutic targets 9 . HF disease‐modifying drugs exert pleiotropic effects, including an associated change in proteomics that additionally helps further our understanding of the mechanisms behind the prognostic benefits of treatment 10,11,12,13 …”

“… 9 HF disease‐modifying drugs exert pleiotropic effects, including an associated change in proteomics that additionally helps further our understanding of the mechanisms behind the prognostic benefits of treatment. 10 , 11 , 12 , 13 …”