title: Thrombopoietin modulates cardiac contractility in vitro and contributes to myocardial depressing activity of septic shock serum.
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-alpha and IL-1beta. 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-alpha and IL-1beta in papillary muscle. In conclusion, TPO negatively modulates cardiac inotropy in vitro and contributes to the myocardial depressing activity of septic shock serum.
authors.affiliation: Department of Clinical Pathophysiology, University of Turin, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Lupia
authors.forename: Tiziana
authors.initials: T
authors.lastname: Spatola
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cuccurullo
authors.forename: Ornella
authors.initials: O
authors.lastname: Bosco
authors.forename: Filippo
authors.initials: F
authors.lastname: Mariano
authors.forename: Angela
authors.initials: A
authors.lastname: Pucci
authors.forename: Roberta
authors.initials: R
authors.lastname: Ramella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alloatti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montrucchio
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000097:blood / Q000503:physiopathology*; D013926:Thrombopoietin / Q000378:metabolism* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001798:Blood Proteins; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D009569:Nitric Oxide; D013926:Thrombopoietin