Intramyocardial VEGF-B 167 Gene Delivery Delays the Progression Towards Congestive Failure in Dogs With Pacing-Induced Dilated Cardiomyopathy
Open accessAbstract
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 P o 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 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-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.
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Successful cardiac transduction in large species requires surgical and catheter-based approaches that preferentially target the heart.
“Successful cardiac transduction in large species requires surgical and catheter-based approaches that can preferentially target the heart”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Pepe, et al., 2010
Canine hearts are typically transduced via methods that specifically target the myocardium such as direct intramyocardial and percutaneous transendocardial injections, which are technically more challenging than simple IP and IV methods.
“Canine hearts are typically transduced via methods that specifically target the myocardium such as direct intramyocardial (Pepe, et al., 2010) and percutaneous transendocardial injections (Bish, Sleeper, et al., 2008) which are technically more challenging than simple IP and IV methods.”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Pepe, et al., 2010
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Small and large animal models in cardiac contraction research: advantages and disadvantages
Milani-Nejad, N., & Janssen, P. M. L. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.10.007 · Cited by 484 · see citing works
- Authors
- Pepe, M., Mamdani, M., Zentilin, L., Csiszar, A., Qanud, K., Zacchigna, S., Ungvari, Z., Puligadda, U., Moimas, S., Xu, X., Edwards, J. G., Hintze, T. H., Giacca, M., & Recchia, F. A.
- Affiliations
- Scuola Superiore Sant'Anna (IT)
- From the Department of Physiology (M.P., M.M., K.Q., X.X., J.G.E., T.H.H., F.A.R.), New York Medical College, Valhalla, NY; International Centre for Genetic Engineering and Biotechnology (L.Z., S.Z., U.P., S.M., M.G.), Trieste, Italy; Reynolds Oklahoma Center on Aging (A.C., Z.U.), Department of Geriatric Medicine, University of Oklahoma Health Science Center, Oklahoma City; and Sector of Medicine (F.A.R.), Scuola Superiore Sant’Anna, Pisa, Italy.
- ORCID
- Venue
- Circulation Research
- Published
- 2010-06-25
- Volume
- 106
- Issue
- 12
- Pages
- 1893-1903
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4879815
- OpenAlex
- W2148120054
- Cited by
- 93
- References
- 45
- Citations by year
- 2025: 2 · 2024: 8 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 7 · 2019: 4 · 2018: 9 · 2017: 5 · 2016: 6 · 2015: 5 · 2014: 10 · 2013: 9 · 2012: 10
- FWCI
- 6.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (P01HL043023, P01-HL74237, P01HL074237, P01 HL 43023)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- VEGF-B, VEGF receptor 1, dilated cardiomyopathy, tachycardia-induced cardiomyopathy, congestive heart failure, cardiomyocyte apoptosis, Akt signaling, GSK3β, FOXO3, angiotensin II, oxidative stress, cardioprotection, AAV gene delivery
- MeSH terms
- Adenoviridae, Animals, Cells, Cultured, Disease Models, Animal, Dogs, Heart Failure, Male, Cardiomyopathies, Myocardium, Gene Transfer Techniques, DNA, Complementary, Oxidative Stress, Disease Progression, Myocytes, Cardiac, Neuropilin-1, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B
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