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Beneficial effects of SR33805 in failing myocardium

Abstract : Aims SR33805, a potent Ca 2+ channel blocker, increases cardiac myofilament Ca 2+ sensitivity in healthy rat cardiomyo-cytes. Therefore, the aim of the present study was to evaluate the effects of SR33805 on contractile properties in ischaemic failing hearts after myocardial infarction (MI) in vivo and in vitro at the cellular level. Methods and results The effect of SR33805 (10 mM) was tested on the excitation-contraction coupling of cardiomyocytes isolated from rat with end-stage heart failure. Cell shortening and Ca 2+ transients were measured in intact cardiomyocytes, while contractile properties were determined in Triton X-100 permeabilized myocytes. Acute treatment with SR33805 restored the MI-altered cell shortening without affecting the Ca 2+ transient amplitude, suggesting an increase of myo-filament Ca 2+ sensitivity in MI myocytes. Indeed, a SR33805-induced sensitization of myofilament activation was found to be associated with a slight increase in myosin light chain-2 phosphorylation and a more significant decrease on troponin I (TnI) phosphorylation. Decreased TnI phosphorylation was related to inhibition of protein kinase A activity by SR33805. Finally, administration of a single intra-peritoneal bolus of SR33805 (20 mg/kg) improved end-systolic strain and fractional shortening of MI hearts. Conclusion The present study indicates that treatment with SR33805 improved contractility of ischaemic failing hearts after MI in the rat by selectively modulating the phosphorylation status of sarcomeric regulatory proteins, which then sensitized the myofilaments to Ca 2+. Our results gave a proof of concept that manipulation of the Ca 2+ sensitivity of sarco-meric regulatory proteins can be used to improve contractility of a failing heart.
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Soumis le : mercredi 22 avril 2020 - 15:09:51
Dernière modification le : samedi 2 mai 2020 - 17:44:11

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Younss Ait Mou, Attila Toth, Cécile Cassan, Daniel Czuriga, Pieter de Tombe, et al.. Beneficial effects of SR33805 in failing myocardium. Cardiovascular Research, Oxford University Press (OUP), 2011, 91 (3), pp.412 - 419. ⟨10.1093/cvr/cvr096⟩. ⟨hal-01824337⟩

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