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(Circulation. 2006;113:2211-2220.)
© 2006 American Heart Association, Inc.

Heart Failure

Thrombopoietin Protects Against In Vitro and In Vivo Cardiotoxicity Induced by Doxorubicin

Karen Li, PhD; Rita Yn Tz Sung, MD; Wei Zhe Huang, MD; Mo Yang, MD, PhD; Nga Hin Pong, MD, MPhil; Shuk Man Lee, MPhil; Wood Yee Chan, PhD; Hailu Zhao, MD; Man Yin To, BSc; Tai Fai Fok, MD; Chi Kong Li, MD; Yuek Oi Wong, PhD; Pak Cheung Ng, MD

From the Departments of Pediatrics (K.L., R.Y.T.S., M.Y., N.H.P., S.M.L., M.Y.T., T.F.F., C.K.L., Y.O.W., P.C.N.), Anatomy (W.Y.C.), and Medicine and Therapeutics (H.Z.), The Chinese University of Hong Kong, Shatin, NT, Hong Kong; and Department of Cardiac Pulmonary Surgery, Shantou University, Shantou, China (W.Z.H.).

Correspondence to Rita Yn Tz Sung, MD, Department of Pediatrics, The Chinese University of Hong Kong, 6th Floor, Clinical Sciences Block, The Prince of Wales Hospital, Shatin, NT, Hong Kong. E-mail yntzsung{at}cuhk.edu.hk

Received May 6, 2005; revision received October 3, 2005; second revision received January 26, 2006; third revision received March 8, 2006; accepted March 9, 2006.

Background— Doxorubicin (DOX) is an important antineoplastic agent. However, the associated cardiotoxicity, possibly mediated by the production of reactive oxygen species, has remained a significant and dose-limiting clinical problem. Our hypothesis is that the hematopoietic/megakaryocytopoietic growth factor thrombopoietin (TPO) protects against DOX-induced cardiotoxicity and might involve antiapoptotic mechanism exerted on cardiomyocytes.

Methods and Results— In vitro investigations on H9C2 cell line and spontaneously beating cells of primary, neonatal rat ventricle, as well as an in vivo study in a mouse model of DOX-induced acute cardiomyopathy, were performed. Our results showed that pretreatment with TPO significantly increased viability of DOX-injured H9C2 cells and beating rates of neonatal myocytes, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. TPO ameliorated DOX-induced apoptosis of H9C2 cells as demonstrated by assays of annexin V, active caspase-3, and mitochondrial membrane potential. In the mouse model, administration of TPO (12.5 µg/kg IP for 3 alternate days) significantly reduced DOX-induced (20 mg/kg) cardiotoxicity, including low blood cell count, cardiomyocyte lesions (apoptosis, vacuolization, and myofibrillar loss), and animal mortality. Using Doppler echocardiography, we observed increased heart rate, fractional shortening, and cardiac output in animals pretreated with TPO compared with those receiving DOX alone.

Conclusions— These data have provided the first evidence that TPO is a protective agent against DOX-induced cardiac injury. We propose to further explore an integrated program, incorporating TPO with other protocols, for treatment of DOX-induced cardiotoxicity and other forms of cardiomyopathy.

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