Raesaenen 2016 Proc Natl Acad Sci U S A

From Bioblast
Publications in the MiPMap
RΓ€sΓ€nen M, Degerman J, Nissinen TA, Miinalainen I, KerkelΓ€ R, Siltanen A, Backman JT, Mervaala E, Hulmi JJ, KivelΓ€ R, Alitalo K (2016) VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection. Proc Natl Acad Sci U S A 113:13144-49.

Β» PMID: 27799559 Open Access

Raesaenen M, Degerman J, Nissinen TA, Miinalainen I, Kerkelae R, Siltanen A, Backman JT, Mervaala E, Hulmi JJ, Kivelae R, Alitalo K (2016) Proc Natl Acad Sci U S A

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. β€’ Keywords: VEGFB, Cancer, Endothelial cell, Heart, Heart failure β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: IE Dublin Miinalainen I, FI Helsinki Mervaala E

Labels: MiParea: Respiration, nDNA;cell genetics, Pharmacology;toxicology  Pathology: Cancer, Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Homogenate 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k 


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