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 high morbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and its evolution. We investigated the cellular phenotype and Ca2+ handling in hearts recapitulating HFpEF criteria. HFpEF was induced in a portion of male Wistar rats four weeks after abdominal aortic banding. These animals had nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hypertrophy, increased LV mass, wall stiffness, impaired active relaxation and passive filling of the left ventricle, enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and the Ca2+ transient larger. Ca2+ cycling was modified with a RyR2 mediated Ca2+ leak from the sarcoplasmic reticulum and impaired Ca2+ extrusion through the Sodium/Calcium exchanger (NCX), which promoted an increase in diastolic Ca2+. The Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2a) and NCX protein levels were unchanged. The phospholamban (PLN) to SERCA2a ratio was augmented in favor of an inhibitory effect 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 an adaptive compensation of Ca2+ cycling. Altogether our findings show that cardiac remodeling in hearts with a HFpEF status differs from that known for heart failure with reduced ejection fraction. These data also underscore the interdependence between systolic and diastolic “adaptations” of Ca2+ cycling with complex compensative interactions between Ca2+ handling partner and regulatory proteins.
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Soumis le : mercredi 22 janvier 2020 - 10:00:30
Dernière modification le : jeudi 23 janvier 2020 - 01:10:26

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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, 2018, 1865 (1), pp.230-242. ⟨10.1016/j.bbadis.2018.08.005⟩. ⟨hal-01856045⟩

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