Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a new potential treatment for anemia, including that caused by ineffective erythropoiesis.

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Buys ES, Cauwels A, Raher MJ, Passeri JJ, Hobai I, Cawley SM, Rauwerdink KM, Thibault H, Sips PY, Thoonen R, ScherrerCrosbie M, Ichinose F, Brouckaert P, Bloch KD. sGC␣ 1␤1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol Heart Circ Physiol 297: H654 -H663, 2009. First published June 5, 2009 doi:10.1152/ajpheart.00367.2009.-Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGC␣1-deficient (sGC␣ 1 Ϫ/Ϫ ) mice to unequivocally determine the role of sGC␣1␤1 in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin-and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGC␣1 Ϫ/Ϫ mice on the C57BL/6 background (sGC␣ 1 Ϫ/ϪB6 mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGC␣ 1 Ϫ/ϪB6 than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca 2ϩ handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGC␣ 1 Ϫ/ϪB6 than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGC␣1compared with WT mice. Together, these findings suggest that cGMP generated by sGC␣1␤1 protects against cardiac dysfunction and mortality in murine inflammatory shock models. soluble guanylate cyclase; left ventricular function; sepsis; mice; nitric oxide IN THE UNITED STATES, sepsis and septic shock develop in 750,000 people annually, of whom Ͼ210,000 die (1), thereby making sepsis a leading cause of death in intensive care units. Invading microorganisms (including gram-positive and -negative bacteria, viruses, fungi, and parasites) induce the release of a wide variety of proinflammatory mediators, causing a systemic inflammatory response syndrome. Systemic inflammatory response syndrome can develop independently of an infection, for example, in cases of pancreatitis or trauma, as well as after cardiopulmonary bypass. It is recognized that refractory hypotension and myocardial depression contribute significantly to the morbidity and mortality of sepsis and septic shock (33,43,57). Similarly, inflammatory shock induced by TNF is characterized by cardiovascular collapse (8, 34).Abundant evidence suggests that nitric oxide (NO) has critical roles in the regulation of myocardial function and structure (5, 24, 48) and blood pressure (23,50). NO plays a pivotal role in cytokine-induced myocardial dysfunction (17, 30, 52), either attenuating or exacerbating the adverse hemodynamic sequelae associated with systemic inflammation. NO is synthes...

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BMC Pharmacology Open AccessPoster presentation sGCα 1 β 1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models