Vascular endothelial growth factor prevents apoptosis and preserves contractile function in hypertrophied infant heart.
BACKGROUND
Cardiac hypertrophy is an adaptive response to increased workload that, if unrelieved, leads to heart failure. It has been reported that cardiomyocyte apoptosis contributes to failure, and that vascular endothelial growth factor (VEGF) treatment of hypertrophied myocardium increases capillary density and improves myocardial perfusion. In this study we hypothesized that VEGF treatment reduces cardiomyocyte apoptosis and thereby preserves myocardial contractile function.


RESULTS
Newborn rabbits underwent aortic banding. At 4 and 6 weeks of age, hypertrophied animals were treated with intrapericardial administration of recombinant VEGF protein. Three groups of animals were investigated: age-matched controls (C), untreated hypertrophied (H), and VEGF-treated hypertrophied hearts (T). Cardiomyocyte apoptosis was determined by TUNEL staining and PARP cleavage (immunoblotting of nuclear extracts) and cardiac function by transthoracic echocardiography. Death attributable to severe heart failure occurred in 14 of 43 untreated and 2 of 29 VEGF-treated animals (P<0.01). TUNEL-positive cardiomyocyte nuclei (n/1000 nuclei) were significantly increased in untreated hearts at 5 weeks (H: 10+/-1.8 versus T: 3+/-0.7) and at 7 weeks (H: 13+/-3.6 versus T: 5+/-1.5; P<0.05). Increased apoptosis in untreated hypertrophy was also confirmed by the presence of PARP cleavage (H: 74+/-7 versus T: 41+/-4 arbitrary densitometry units; P<0.05). VEGF treatment preserved left ventricular mass, prevented dilation (T: 1.01+/-0.06 versus H: 0.77+/-0.07; P<0.05), and preserved contractility indices compared with untreated hearts.


CONCLUSIONS
Lack of adaptive capillary growth impairs myocardial perfusion and substrate delivery in hypertrophying myocardium. VEGF treatment reduces myocardial apoptosis and prolongs survival in a model of severe progressive left ventricular hypertrophy. Promoting capillary growth with VEGF reduces apoptosis, preserves myocardial contractile function, and delays the onset of failure in pressure-loaded infant myocardium.
Friehs
Ingeborg
I
Department of Cardiac Surgery, Perioperative & Pain Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave, Bader 279, Boston, Massachusetts 02115, USA.
Barillas
Rodrigo
R
Vasilyev
Nikolay V
NV
Roy
Nathalie
N
McGowan
Francis X
FX
del Nido
Pedro J
PJ
D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008026:Ligation; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000627:therapeutic use*
D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D011065:Poly(ADP-ribose) Polymerases