Published Online
on May 1, 2006

A more recent version of this article appeared on May 9, 2006

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Submitted on October 3, 2005
Revised on March 8, 2006
Accepted on March 9, 2006

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, and 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.).

^* To whom correspondence should be addressed. E-mail: yntzsung{at}cuhk.edu.hk.

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.

Key words: apoptosis • cardiomyopathy • doxorubicin • echocardiography • thrombopoietin

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