Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.

Abstract

VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but, unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VAs). VEGF-B knockout, alpha myosin heavy-chain promoter (αMHC)-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied. Immunostaining showed a 2-fold increase in the number of nerves per field (76 vs. 39 in controls, p < 0.001) and an abnormal nerve distribution in the hypertrophic hearts of 11- to 20-month-old αMHC-VEGF-B mice. AdVEGF-B186 gene transfer (GT) led to local sprouting of nerve endings in pig myocardium (141 vs. 78 nerves per field in controls, p < 0.05). During dobutamine stress, 60% of the αMHC-VEGF-B hypertrophic mice had arrhythmias as compared to 7% in controls, and 20% of the AdVEGF-B186-transduced pigs and 100% of the combination of AdVEGF-B186- and AdsVEGFR-1-transduced pigs displayed VAs and even ventricular fibrillation. AdVEGF-B186 GT significantly increased the risk of sudden cardiac death in pigs when compared to any other GT with different VEGFs (hazard ratio, 500.5; 95% confidence interval [CI] 46.4-5,396.7; p < 0.0001). In gene expression analysis, VEGF-B induced the upregulation of Nr4a2, ATF6, and MANF in cardiomyocytes, molecules previously linked to nerve growth and differentiation. Thus, high AdVEGF-B186 overexpression induced nerve growth in the adult heart via a VEGFR-1 signaling-independent mechanism, leading to an increased risk of VA and sudden cardiac death.

• Authors: Johanna Lähteenvuo, Olli-Pekka Hätinen, Antti Kuivanen, Jenni Huusko, Jussi Paananen, Markku Lähteenvuo, Jussi Nurro, Marja Hedman, Juha Hartikainen, Nihay Laham-Karam, Petri Mäkinen, Markus Räsänen, Kari Alitalo, Anthony Rosenzweig, Seppo Ylä-Herttuala
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 28 Issue 7 Pg. 1731-1740 (07 08 2020) ISSN: 1525-0024 [Electronic] United States
• PMID: 32243833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Recombinant Proteins
• Vascular Endothelial Growth Factor B
• vascular endothelial growth factor B, mouse
• Myosin Heavy Chains

Topics

• Animals
• Animals, Genetically Modified
• Arrhythmias, Cardiac (genetics, metabolism, pathology)
• Dependovirus (genetics)
• Disease Notification
• Female
• Gene Knockout Techniques
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Male
• Mice
• Myosin Heavy Chains (genetics)
• Promoter Regions, Genetic
• Recombinant Proteins (metabolism)
• Swine
• Sympathetic Nervous System (metabolism, pathology)
• Transduction, Genetic
• Up-Regulation
• Vascular Endothelial Growth Factor B (adverse effects, genetics, metabolism)