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-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)-3 beta 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. (Circ Res. 2010;106:1893-1903.)
Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy
Pepe, Martino;
2010-01-01
Abstract
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-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)-3 beta 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. (Circ Res. 2010;106:1893-1903.)I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
