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Early calcium handling imbalance in pressure overload-induced heart failure with nearly normal left ventricular ejection fraction

Abstract : Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome associated with highmorbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and itsevolution. We investigated the cellular phenotype and Ca2+handling in hearts recapitulating HFpEF criteria.HFpEF was induced in a portion of maleWistarrats four weeks after abdominal aortic banding. These animalshad nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hyper-trophy, increased LV mass, wall stiffness, impaired active relaxation and passivefilling of the left ventricle,enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and theCa2+transient larger. Ca2+cycling was modified with a RyR2 mediated Ca2+leak from the sarcoplasmic re-ticulum and impaired Ca2+extrusion through the Sodium/Calcium exchanger (NCX), which promoted an in-crease in diastolic Ca2+. The Sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA2a) and NCX proteinlevels were unchanged. The phospholamban (PLN) to SERCA2a ratio was augmented in favor of an inhibitoryeffect on the SERCA2a activity. Conversely, PLN phosphorylation at the calmodulin-dependent kinase II(CaMKII)-specific site (PLN-Thr17), which promotes SERCA2A activity, was increased as well, suggesting anadaptive compensation of Ca2+cycling. Altogether ourfindings show that cardiac remodeling in hearts with aHFpEF status differs from that known for heart failure with reduced ejection fraction. These data also underscorethe interdependence between systolic and diastolic“adaptations”of Ca2+cycling with complex compensativeinteractions between Ca2+handling partner and regulatory proteins.
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Soumis le : mercredi 22 janvier 2020 - 10:00:30
Dernière modification le : mardi 26 mai 2020 - 03:40:53
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2018 Rouhana et al., Early cal...
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Sarah Rouhana, Charlotte Farah, Jérôme Roy, Amanda Finan, Glaucy Rodrigues de Araujo, et al.. Early calcium handling imbalance in pressure overload-induced heart failure with nearly normal left ventricular ejection fraction. Biochimica et Biophysica Acta - Molecular Basis of Disease, Elsevier, 2019, 1865 (1), pp.230-242. ⟨10.1016/j.bbadis.2018.08.005⟩. ⟨hal-01856045⟩



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