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VEGF-R1 AGONISTS PROTECT CARDIOMYOCYTES AGAINST OXIDATIVE STRESS
Hurst, MaryKathryn
Hurst, MaryKathryn
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Thesis/Dissertation
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2014
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Biomedical Sciences
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http://dx.doi.org/10.34944/dspace/3024
Abstract
VEGF-R1 Agonists protect Cardiomyocytes against Oxidative Stress Background: Selective agonists of the vascular endothelial growth factor receptor 1 (VEGFR-1) display cytoprotective and anti-apoptotic effects in the failing heart. Since a major determinant of myocardial damage in heart failure is oxidative stress, we tested the hypothesis that VEGFR-1 mediates anti-oxidant mechanisms. Methods: Freshly prepared cardiac tissue slices were obtained from dogs with pacing-induced heart failure that had been previously transduced with the VEGFR-1 selective ligand VEGF-B. Dihydroetidium (DHE) fluorescence was used to monitor the production of reactive oxygen species. In addition, cultured rat neonatal cardiomyocytes were tested with two major mediators causing oxidative stress in the failing heart, namely angiotensin II (10-8 M for 24 hours) and norepinephrine (50 µM for 24 hours). The experiments were performed in the absence or in the presence of the VEGFR-1 agonists VEGF-B and PlGF or of the mixed VEGFR-1 and VEGFR-2 agonist VEGF-A or of the selective VEGFR-2 agonist VEGF-E. Mitochondrial superoxide and cytosolic hydrogen peroxide were measured, respectively, as MitoSox and DCF fluorescence intensity. Results: In fresh cardiac tissue slices, DHE fluorescence indicated that superoxide production was significantly reduced in VEGF-B treated hearts compared to control failing hearts. In cultured cardiomyocytes, VEGF-B and PlGF, but not VEGF-A or VEGF-E, prevented mitochondrial superoxide and cytosolic hydrogen peroxide overproduction in response to angiotensin II or norepinephrine. These findings were consistent with the induction of mitochondrial superoxide dismutase and glutathione peroxidase-1 overexpression in VEGF-B-treated cells. Conclusions: VEGF-R1 activation can reduce oxidative stress both in vivo and in vitro. Our results provide insights in the cardioprotective mechanisms activated by VEGF-B gene therapy in the failing heart.
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