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: Markus Räsänen, Joni Degerman, Tuuli A Nissinen, Ilkka Miinalainen, Risto Kerkelä, Antti Siltanen, Janne T Backman, Eero Mervaala, Juha J Hulmi, Riikka Kivelä, Kari Alitalo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 46 Pg. 13144-13149 (11 15 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27799559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Vascular Endothelial Growth Factor B
• Doxorubicin

Topics

• Adipose Tissue, White (metabolism)
• Animals
• Antibiotics, Antineoplastic (adverse effects, blood, pharmacokinetics)
• Apoptosis (drug effects)
• Cardiotoxicity (pathology, physiopathology, therapy)
• Cell Line, Tumor
• DNA Damage
• Doxorubicin (adverse effects, blood, pharmacokinetics)
• Endothelial Cells (drug effects)
• Genetic Therapy
• Liver (metabolism)
• Male
• Mice, Inbred C57BL
• Mitochondria, Heart (drug effects, metabolism)
• Myocardium (metabolism, pathology)
• Neoplasms (drug therapy, metabolism, pathology)
• Vascular Endothelial Growth Factor B (blood, genetics, metabolism)