Phosphomimetic endothelial nitric oxide synthase-loaded microbubbles-mediated cardiac shock wave transfection therapy for angiogenesis in the ischemic myocardium

Abstract

Abstract Background Cardiac shock wave therapy is a potential and effective remedy to promote revascularization in the ischemic myocardium of patients with refractory coronary heart disease (CHD). Although gene therapy holds great promise as a treatment for coronary heart disease, current clinical application is hampered by the development of safe and efficient systems for local gene delivery to a specific tissue or organ. Purpose In this study, we developed an experimental pulsed- focused electrohydraulic shock wave therapy system and investigated its effectiveness on myocardial angiogenesis in the hypercholesterolemic rabbit accompanied by phosphomimetic endothelial nitric oxide synthase-loaded microbubbles administration, wherein a high resolution diagnostic ultrasound is adjuncted with the therapy system, with a goal of increased safety. Methods Briefly, New Zealand white rabbits underwent 2% cholesterol rich diet injury for sixteen weeks. Histopathology results showed the formation of foam cells-rich soft atherosclerotic plaques with severe stenosis in all of the rabbits' coronary arteries. Then treatment group underwent extracorporeal electrohydraulic pulsed-focused shock waves (25kV, 0.5Hz, 150 pulses) accompanied by phosphomimetic endothelial nitric oxide synthase-loaded PESDA (Perfluorocarbon Exposed Sonicated Dextrose Albumin) microbubbles (100 ml/kg, 2.5x105 bubbles/ml) administration. Results Results from ultrasonography and histopathology showed a significant increase in the mean value for myocardial neovessels density in the treatment group compared with the control group (p<0.05). Conclusion Enhanced angiogenesis and sonoporation effect of electrohydraulic shock wave therapy, induced by inertial collapsed microbubbles, accompanied by phosphomimetic endothelial nitric oxide synthase-mediated shock wave transfection therapy, can cause to enhance the nitric oxide synthesis and VEGF, interleukin8 (IL8), stromal cell- derived factor 1 (SDF1) and matrix metalloproteinase 9 (MMP9) secretion in the hypercholesterolemic rabbits' coronary arteries, resulting in the differentiation and recruitment of endothelial progenitor cells (EPCs), promotion of revascularization in the ischemic myocardium and improvement of the cardiac function. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab