Creatine Kinase-Overexpression Improves Myocardial Energetics, Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

PLoS One

Vadappuram P. Chacko¹  Michelle K. Leppo¹  Ashish Gupta¹  Robert G. Weiss²  Yibin Wang³  Cory Rohlfsen³  Charles Steenbergen⁴ 

[1] Department of Medicine, Division of Cardiology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Department of Radiology, Division of Magnetic Resonance Research, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;University of California Los Angeles, Los Angeles, California, United States of America

关键词: Heart;    Energy metabolism;    Mouse models;    Phosphates;    Magnetic resonance imaging;    Muscle contraction;    Heart failure;    Mitochondria;   

DOI  :  10.1371/journal.pone.0074675

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5mg/kg) administration using in vivo31P MRS and 1H MRI. In control animals, in vivo cardiac energetics were reduced at 7 weeks of DOX protocol and this was followed by a mild but significant reduction in left ventricular ejection fraction (EF) at 8 weeks of DOX, as compared to baseline. At baseline, CK-M overexpression (CK-M-OE) increased rates of ATP synthesis through cardiac CK (CK flux) but did not affect contractile function. Following DOX however, CK-M-OE hearts had better preservation of creatine phosphate and higher CK flux and higher EF as compared to control DOX hearts. Survival after DOX administration was significantly better in CK-M-OE than in control animals (p<0.02). Thus CK-M-OE attenuates the early decline in myocardial high-energy phosphates and contractile function caused by chronic DOX administration and increases survival. These findings suggest that CK impairment plays an energetic and functional role in this DOX-cardiotoxicity model and suggests that metabolic strategies, particularly those targeting CK, offer an appealing new strategy for limiting DOX-associated cardiotoxicity.

【 授权许可】

CC BY