PRECLINCAL RESEARCH
Cellular, but not direct, adenoviral delivery of vascular endothelial growth factor results in improved left ventricular function and neovascularization in dilated ischemic cardiomyopathy
Arman Askari, MD*,
Samuel Unzek, MD ,
Corey K. Goldman, MD, PhD,
Stephen G. Ellis, MD, FACC*,
James D. Thomas, MD, FACC*,
Paul E. DiCorleto, PhD,
Eric J. Topol, MD, FACC* and
Marc S. Penn, MD, PhD, FACC*,*
* Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, USA
Department of Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, USA
Manuscript received August 26, 2003;
revised manuscript received November 7, 2003,
accepted December 23, 2003.
* Reprint requests and correspondence: Dr. Marc S. Penn, Experimental Animal Laboratory, Departments of Cardiovascular Medicine and Cell Biology, Cleveland Clinic Foundation, NC10, Cleveland, Ohio 44195, USA.
pennm{at}ccf.org
OBJECTIVES: We sought to compare the effects on angiogenesis and left ventricular (LV) function of adenoviral vascular endothelial growth factor-165 (AdVEGF-165) gene delivery by direct injection of AdVEGF-165 to the transplantation of skeletal myoblasts (SKMB) transfected with AdVEGF-165 in a rat model of ischemic cardiomyopathy.
BACKGROUND: Angiogenesis offers the potential for treating ischemic cardiomyopathy. However, the optimal method of delivering angiogenic factors for neovascularization remains undetermined. With the increased clinical interest in cell therapy for the treatment of LV dysfunction, SKMB transplantation may serve as a means of gene transfer.
METHODS: Two months after left anterior descending coronary artery ligation, rats received either injection of an adenoviral construct encoding VEGF-165, or 1 million SKMB transfected with AdLuciferase (AdLuc) or AdVEGF-165. Cardiac function was assessed echocardiographically, and neovascularization was assessed histologically four weeks after therapy.
RESULTS: Neovascularization was significantly increased by both AdVEGF delivery strategies (100 ± 7% and 185 ± 33% increase in vascular density compared with SKMB alone, respectively). However, cell-based delivery, but not direct injection of AdVEGF-165, resulted in increased cardiac function (73.5 ± 12.6% and 1.5 ± 8.8% increase in shortening fraction compared with saline control; AdLuc-transfected SKMB: 29.4 ± 15.0%). The improved function was not due to increased engraftment of VEGF expressing SKMB. Rather, improved function correlated with less apoptosis in the border zone in those animals that received AdVEGF-165 expressing SKMB.
CONCLUSION: Our data demonstrate that cell-based delivery of VEGF leads to an improved treatment effect over direct adenoviral injection, and suggest that already developed adenoviral vectors that encode secreted factors could potentially offer greater efficacy in combination with SKMB transplantation.
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Abbreviations and Acronyms
| | AdLuc | = adenoviral Luciferase | | AdVEGF-165 | = adenoviral vascular endothelial growth factor-165 | | LAD | = left anterior descending coronary artery | | LV | = left ventricle/ventricular | | MI | = myocardial infarction | | SKMB | = skeletal myoblasts |
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