title: VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection.
abstract: 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.
authors: Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.|Translational Cancer Biology Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Markus
authors: M
authors: Räsänen
authors: Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.|Translational Cancer Biology Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Joni
authors: J
authors: Degerman
authors: Department of Biology of Physical Activity, University of Jyväskylä, 40014 Jyvaskyla, Finland.
authors: Tuuli A
authors: TA
authors: Nissinen
authors: Medical Research Center Oulu, Research Unit of Biomedicine, University of Oulu and University Hospital Oulu, 90014 Oulu, Finland.
authors: Ilkka
authors: I
authors: Miinalainen
authors: Medical Research Center Oulu, Research Unit of Biomedicine, University of Oulu and University Hospital Oulu, 90014 Oulu, Finland.
authors: Risto
authors: R
authors: Kerkelä
authors: Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
authors: Antti
authors: A
authors: Siltanen
authors: Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland.
authors: Janne T
authors: JT
authors: Backman
authors: Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
authors: Eero
authors: E
authors: Mervaala
authors: Department of Biology of Physical Activity, University of Jyväskylä, 40014 Jyvaskyla, Finland.|Department of Physiology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland.
authors: Juha J
authors: JJ
authors: Hulmi
authors: Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; kari.alitalo@helsinki.fi riikka.kivela@helsinki.fi.|Translational Cancer Biology Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Riikka
authors: R
authors: Kivelä
authors: Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland; kari.alitalo@helsinki.fi riikka.kivela@helsinki.fi.|Translational Cancer Biology Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Kari
authors: K
authors: Alitalo
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D042783:Endothelial Cells / Q000187:drug effects; D015316:Genetic Therapy; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D042561:Vascular Endothelial Growth Factor B / Q000097:blood / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D042561:Vascular Endothelial Growth Factor B; D004317:Doxorubicin
keywords: VEGFB; cancer; endothelial cell; heart; heart failure