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

TY - JOUR

T1 - Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy

AU - Pepe, Martino

AU - Mamdani, Mohammed

AU - Zentilin, Lorena

AU - Csiszar, Anna

AU - Qanud, Khaled

AU - Zacchigna, Serena

AU - Ungvari, Zoltan

AU - Puligadda, Uday

AU - Moimas, Silvia

AU - Xu, Xiaobin

AU - Edwards, John G.

AU - Hintze, Thomas H.

AU - Giacca, Mauro

AU - Recchia, Fabio A.

PY - 2010/6/25

Y1 - 2010/6/25

N2 - Rationale: 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-B167 cDNA (10 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 Po2. 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 α-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)-3β 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-B167 exerted a compensatory receptor stimulation. The cytoprotective effects of VEGF-B167 were further elucidated in cultured rat neonatal cardiomyocytes exposed to 10-8 mol/L angiotensin II: VEGF-B167 prevented oxidative stress, loss of mitochondrial membrane potential, and, consequently, apoptosis. Conclusions: We determined a novel, angiogenesis-unrelated cardioprotective effect of VEGF-B167 in nonischemic dilated cardiomyopathy, which limits apoptotic cell loss and delays the progression toward failure.

AB - Rationale: 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-B167 cDNA (10 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 Po2. 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 α-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)-3β 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-B167 exerted a compensatory receptor stimulation. The cytoprotective effects of VEGF-B167 were further elucidated in cultured rat neonatal cardiomyocytes exposed to 10-8 mol/L angiotensin II: VEGF-B167 prevented oxidative stress, loss of mitochondrial membrane potential, and, consequently, apoptosis. Conclusions: We determined a novel, angiogenesis-unrelated cardioprotective effect of VEGF-B167 in nonischemic dilated cardiomyopathy, which limits apoptotic cell loss and delays the progression toward failure.

KW - gene therapy

KW - heart failure

KW - vascular endothelial growth factors

UR - http://www.scopus.com/inward/record.url?scp=77954214321&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.110.220855

DO - 10.1161/CIRCRESAHA.110.220855

M3 - Article

C2 - 20431055

AN - SCOPUS:77954214321

SN - 0009-7330

VL - 106

SP - 1893

EP - 1903

JO - Circulation Research

JF - Circulation Research

IS - 12

ER -