期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13144-13149
DOI：10.1073/pnas.1616168113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe cardiotoxicity of anthracyclines is a major problem in cancer chemotherapy, and its alleviation would improve the life expectancy of cancer patients. This study shows that vascular endothelial growth factor-B (VEGF-B) gene therapy can be used to prevent the cardiotoxicity of doxorubicin (DOX). VEGF-B inhibited DOX-induced cardiac atrophy, protected endothelial cells from apoptosis, and preserved the myocardial capillary network. Importantly, DOX-induced whole body wasting (cachexia), which both impairs the quality of life and increases drug toxicity in patients as well as decreases their survival, was inhibited by VEGF-B treatment in the DOX-treated mice. Additional preclinical studies are needed for development of the VEGF-B gene therapy for cardiac protection in patients. Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.
