ArticlePloS one2025
Epac1 increases myosin regulatory light-chain phosphorylation, energetic cost of contraction, and susceptibility to heart failure.
Article in PloS one, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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1 citing paper in PubMed.
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Authors and funding
13 authors.
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No grant is acknowledged in the PubMed record.
Abstract
β-Adrenergic receptor (β-AR) stimulation of the heart, leading to increased cardiac output, is mediated by cyclic AMP (cAMP), which induces protein kinase A (PKA)-mediated phosphorylation of the myofilament proteins troponin I (TnI) and myosin binding protein-C (MyBP-C). The aim of this study was to investigate the contribution of the exchange protein activated by cAMP (Epac1), a PKA-independent cAMP effector, to the response of cardiac myofilaments to β-AR stimulation. The calcium sensitivity of force and ATPase activity, and the tension cost (ATPase activity/force) were significantly greater in skinned myocardium from transgenic mice specifically overexpressing Epac1 in the heart (Epac1TG) and wild-type (WT) mice treated with 8CPT-AM, an Epac-selective cAMP analogue, as compared with non-transgenic (NTG) or control mice, respectively. In addition, myosin regulatory light chain (RLC) phosphorylation was significantly greater in Epac1TG and WT mice treated with 8CPT-AM than in NTG or control mice via phospholipase C/phosphokinase C, without any change in the phosphorylation of TnI or MyBP-C. We also examined the effects of chronic β-AR stimulation on cardiac function in Epac1TG. The left ventricular ejection fraction was significantly decreased from baseline in both NTG and Epac1TG after isoproterenol infusion (60 mg/kg/day for 1 week), but the magnitude of the decrease was much greater in Epac1TG. Our results suggest that Epac1 activation might induce an imbalance between force-generating capacity and ATPase activity in skinned myocardium. This could increase oxygen consumption and the energetic cost of contraction in living myocardium under conditions of chronic β-AR stimulation, leading to the development of heart failure.
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