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


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.
Pepe
Martino
M
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Mamdani
Mohammed
M
Zentilin
Lorena
L
Csiszar
Anna
A
Qanud
Khaled
K
Zacchigna
Serena
S
Ungvari
Zoltan
Z
Puligadda
Uday
U
Moimas
Silvia
S
Xu
Xiaobin
X
Edwards
John G
JG
Hintze
Thomas H
TH
Giacca
Mauro
M
Recchia
Fabio A
FA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000150:complications* / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D039942:Neuropilin-1 / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics* / Q000378:metabolism*
D018076:DNA, Complementary; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor