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Selective SERCA2a activator as a candidate for chronic heart failure therapy
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  • Martina Arici,
  • Shih-Che Hsu,
  • Mara Ferrandi,
  • Paolo Barassi,
  • Carlotta Ronchi,
  • Eleonora Torre,
  • Andrea Luraghi,
  • Gwo-Jyh Chang,
  • Patrizia Ferrari,
  • Giuseppe Bianchi,
  • Franchesco Peri,
  • Antonio Zaza,
  • Marcella Rocchetti
Martina Arici
Universita degli Studi di Milano-Bicocca
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Shih-Che Hsu
CVie Therapeutics Limited
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Mara Ferrandi
Windtree Therapeutics Inc
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Paolo Barassi
Windtree Therapeutics Inc
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Carlotta Ronchi
Universita degli Studi di Milano-Bicocca
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Eleonora Torre
Universita degli Studi di Milano-Bicocca
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Andrea Luraghi
Universita degli Studi di Milano-Bicocca
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Gwo-Jyh Chang
College of Medicine, Chang Gung University
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Patrizia Ferrari
Windtree Therapeutics Inc
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Giuseppe Bianchi
Windtree Therapeutics Inc
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Franchesco Peri
Università degli Studi di Milano-Bicocca
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Antonio Zaza
Università degli Studi di Milano-Bicocca
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Marcella Rocchetti
Universita degli Studi di Milano-Bicocca

Corresponding Author:[email protected]

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Abstract

Background and Purpose. The sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) depression substantially contributes to diastolic dysfunction in heart failure (HF), suggesting that SERCA2a stimulation may be a “causal” HF therapy. Istaroxime is a drug endowed with both a SERCA2a stimulatory activity and a Na+/K+ pump inhibitory activity for the acute HF treatment. Its main metabolite PST3093 shows a more favorable therapeutic profile as compared to the parent drug, but it is still unsuitable for chronic usage. Novel PST3093 derivatives have been recently developed for oral (chronic) HF treatment; compound 8 was selected among them and here characterized. Experimental Approach. Effects of compound 8 were evaluated in a context of SERCA2a depression, by using streptozotocin-treated rats, a well-known model of diastolic dysfunction. The impact of SERCA2a stimulation by compound 8 was assessed both at the cellular level ad in vivo, following i.v. infusion (acute effects) or oral administration (chronic effects). Key Results. As expected from SERCA2a stimulation, compound 8 induced SR Ca2+ compartmentalization in STZ myocytes. In-vivo echocardiographic analysis during i.v. infusion and after repeated oral administration of compound 8, detected a significant improvement of diastolic function. Moreover, compound 8 did not affect electrical activity of healthy guinea-pig myocytes, in line with the absence of off-target effects. Finally, compound 8 was well tolerated in mice with no evidence of acute toxicity. Conclusion and Implications. The pharmacological evaluation of compound 8 indicates that it may be a safe and selective drug for a “causal” treatment of chronic HF by restoring SERCA2a activity.