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Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy.

AbstractRATIONALE:
Vascular endothelial growth factor (VEGF)-B selectively binds VEGF receptor (VEGFR)-1, a receptor that does not mediate angiogenesis, and is emerging as a major cytoprotective factor.
OBJECTIVE:
To test the hypothesis that VEGF-B exerts non-angiogenesis-related cardioprotective effects in nonischemic dilated cardiomyopathy.
METHODS AND RESULTS:
AAV-9-carried VEGF-B(167) cDNA (10(12) genome copies) was injected into the myocardium of chronically instrumented dogs developing tachypacing-induced dilated cardiomyopathy. After 4 weeks of pacing, green fluorescent protein-transduced dogs (AAV-control, n=8) were in overt congestive heart failure, whereas the VEGF-B-transduced (AAV-VEGF-B, n=8) were still in a well-compensated state, with physiological arterial Po(2). Left ventricular (LV) end-diastolic pressure in AAV-VEGF-B and AAV-control was, respectively, 15.0+/-1.5 versus 26.7+/-1.8 mm Hg and LV regional fractional shortening was 9.4+/-1.6% versus 3.0+/-0.6% (all P<0.05). VEGF-B prevented LV wall thinning but did not induce cardiac hypertrophy and did not affect the density of alpha-smooth muscle actin-positive microvessels, whereas it normalized TUNEL-positive cardiomyocytes and caspase-9 and -3 activation. Consistently, activated Akt, a major negative regulator of apoptosis, was superphysiological in AAV-VEGF-B, whereas the proapoptotic intracellular mediators glycogen synthase kinase (GSK)-3beta and FoxO3a (Akt targets) were activated in AAV-control, but not in AAV-VEGF-B. Cardiac VEGFR-1 expression was reduced 4-fold in all paced dogs, suggesting that exogenous VEGF-B(167) exerted a compensatory receptor stimulation. The cytoprotective effects of VEGF-B(167) were further elucidated in cultured rat neonatal cardiomyocytes exposed to 10(-8) mol/L angiotensin II: VEGF-B(167) prevented oxidative stress, loss of mitochondrial membrane potential, and, consequently, apoptosis.
CONCLUSIONS:
We determined a novel, angiogenesis-unrelated cardioprotective effect of VEGF-B(167) in nonischemic dilated cardiomyopathy, which limits apoptotic cell loss and delays the progression toward failure.
AuthorsMartino Pepe, Mohammed Mamdani, Lorena Zentilin, Anna Csiszar, Khaled Qanud, Serena Zacchigna, Zoltan Ungvari, Uday Puligadda, Silvia Moimas, Xiaobin Xu, John G Edwards, Thomas H Hintze, Mauro Giacca, Fabio A Recchia
JournalCirculation research (Circ Res) Vol. 106 Issue 12 Pg. 1893-903 (Jun 25 2010) ISSN: 1524-4571 [Electronic] United States
PMID20431055 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA, Complementary
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor B
  • Neuropilin-1
  • Receptors, Vascular Endothelial Growth Factor
Topics
  • Adenoviridae (genetics)
  • Animals
  • Cardiomyopathies (complications, metabolism)
  • Cells, Cultured
  • DNA, Complementary (genetics)
  • Disease Models, Animal
  • Disease Progression
  • Dogs
  • Gene Transfer Techniques
  • Heart Failure (metabolism, prevention & control)
  • Male
  • Myocardium (metabolism, pathology)
  • Myocytes, Cardiac (metabolism, pathology)
  • Neuropilin-1 (metabolism)
  • Oxidative Stress (physiology)
  • Receptors, Vascular Endothelial Growth Factor (metabolism)
  • Vascular Endothelial Growth Factor A (metabolism)
  • Vascular Endothelial Growth Factor B (genetics, metabolism)

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