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Thrombopoietin modulates cardiac contractility in vitro and contributes to myocardial depressing activity of septic shock serum

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Abstract

Thrombopoietin (TPO) is a humoral growth factor that has been shown to increase platelet activation in response to several agonists. Patients with sepsis have increased circulating TPO levels, which may enhance platelet activation, potentially participating to the pathogenesis of multi-organ failure. Aim of this study was to investigate whether TPO affects myocardial contractility and participates to depress cardiac function during sepsis. We showed the expression of the TPO receptor c-Mpl on myocardial cells and tissue by RT-PCR, immunofluorescence and western blotting. We then evaluated the effect of TPO on the contractile function of rat papillary muscle and isolated heart. TPO did not change myocardial contractility in basal conditions, but, when followed by epinephrine (EPI) stimulation, it blunted the enhancement of contractile force induced by EPI both in papillary muscle and isolated heart. An inhibitor of TPO prevented TPO effect on cardiac inotropy. Treatment of papillary muscle with pharmacological inhibitors of phosphatidylinositol 3-kinase, NO synthase, and guanilyl cyclase abolished TPO effect, indicating NO as the final mediator. We finally studied the role of TPO in the negative inotropic effect exerted by human septic shock (HSS) serum and TPO cooperation with TNF-α and IL-1β. Pre-treatment with the TPO inhibitor prevented the decrease in contractile force induced by HSS serum. Moreover, TPO significantly amplified the negative inotropic effect induced by TNF-α and IL-1β in papillary muscle. In conclusion, TPO negatively modulates cardiac inotropy in vitro and contributes to the myocardial depressing activity of septic shock serum.

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Acknowledgments

This work was supported by Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) ex-60% to GM and GA, and Progetto di Ricerca Sanitaria Finalizzata—Regione Piemonte to GM, GA, and EL.

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The authors declare that they have no conflict of interest.

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Author notes

  1. Tiziana Spatola

    Present address: Department of Medicine and Experimental Oncology and Molecular Biotechnology Center, University of Turin, Turin, Italy

Authors and Affiliations

  1. Department of Clinical Pathophysiology, University of Turin, Via Genova 3, 10126, Turin, Italy

    Enrico Lupia, Tiziana Spatola, Alessandra Cuccurullo, Ornella Bosco & Giuseppe Montrucchio

  2. Department of Animal and Human Biology, University of Turin, Turin, Italy

    Roberta Ramella & Giuseppe Alloatti

  3. Department of Medicine Area, Nephrology and Dialysis Unit, CTO Hospital, Turin, Italy

    Filippo Mariano

  4. Department of Pathology, Regina Margherita Hospital, ASO OIRM-S.Anna, Turin, Italy

    Angela Pucci

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  1. Enrico Lupia
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  9. Giuseppe Montrucchio
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Correspondence to Giuseppe Montrucchio.

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G. Alloatti and G. Montrucchio equally contributed.

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Lupia, E., Spatola, T., Cuccurullo, A. et al. Thrombopoietin modulates cardiac contractility in vitro and contributes to myocardial depressing activity of septic shock serum. Basic Res Cardiol 105, 609–620 (2010). https://doi.org/10.1007/s00395-010-0103-6

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