Thrombopoietin emerges as a new haematopoietic cytokine that confers cardioprotection against acute myocardial infarction.

Colony stimulating factors (CSFs), also called haematopoietic growth factors, are circulating cytokines that regulate the bone marrow production of red cells, white cells, and platelets. CSFs have also been reported to act on stem cells to regulate lineage-specific differentiation. Erythropoietin (EPO) controls red cell production and has been utilized in recombinant form for the treatment of anaemia in patients with end-stage renal disease since 1988. Granulocyte CSF (G-CSF) acts on haematopoietic stem cells to regulate neutrophil progenitor proliferation and differentiation. G-CSF is routinely used to mobilize stem cells in normal patients for transplantation of cells into patients with haematological malignancies, or in the patients themselves. Several recent reports have suggested that these cytokines possess properties that extend beyond their haematopoietic properties, such as the ability to protect the heart against injury caused by ischaemia and reperfusion (I/R). Baker et al. now demonstrate for the first time in this issue of Cardiovascular Research that a third haematopoietic growth factor, thrombopoietin (TPO), is able to provide cardioprotection against myocardial I/R injury in a rat model by mechanisms independent of its haematopoietic properties. TPO affects nearly all aspects of platelet production, from self-renewal and expansion of haematopoietic stem cells, through stimulation of the proliferation of megakaryocyte progenitor cells, to support the maturation of these cells into platelet-producing cells. Since its purification in 1994, TPO has been used to treat thrombocytopenia caused by many conventional chemotherapy regimens. Recently, TPO was reported to protect against doxorubicin-induced cardiotoxicity. The current study expands on the reported cardioprotective actions of TPO and provides the first evidence that TPO protects against acute myocardial infarction. The authors first demonstrated that the receptor for TPO, c-Mpl, is present in the heart and localized to the myocytes. Using both in vitro and in vivo models of global and regional myocardial I/R, they found that a single treatment with recombinant human TPO prior to ischaemia exerts an immediate protective effect, as manifested by a reduction in myocardial cell death and an improved recovery of ventricular function following ischaemia. This immediate cardioprotective effect of TPO was found to be concentrationand dose-dependent with an optimal protection occurring at 1.0 ng/mL in vitro and 0.05 mg/kg (i.v.) in vivo. In the clinic, patients generally receive medical treatment for acute myocardial infarction after the onset of symptoms. Therefore, in subsequent experiments, the authors investigated if a single injection of TPO (0.05 mg/kg, i.v.) administered either 15 min after the onset of ischaemia or 10 s after the onset of reperfusion would protect the myocardium. In both instances, TPO reduced infarct size to the same degree as the administration prior to ischaemia. The authors then demonstrated that TPO-induced cardioprotection was mediated by Janus family of tyrosine kinase 2 (JAK-2), signal transducers and activators of transcription 3 (STAT-3), mitogen-activated protein kinases (MAPK, p42/44), sarcolemmal ATP-sensitive potassium (KATP) channels and mitochondrial KATP channels. The increased resistance to injury was observed immediately after treatment with TPO, indicating that the induction of new genes is not necessary for its cardioprotective effect to be manifested. Importantly, TPO confers its protective effect against injury from myocardial I/R without increasing platelet levels or haematocrit, which further suggests that it has direct cardioprotective properties, independent of its ability to promote platelet production. Potentially, the most important finding of the current study by Baker et al. is that like EPO, TPO appears to provide cardioprotection by activating the JAK/STAT signalling cascade and KATP channels. 8 The cardioprotective signalling pathway is conceivably initiated by the binding of TPO to its receptor, c-Mpl, which then, like other haematopoietic cytokine receptors, transmits numerous biochemical The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.