Abstract 15828: Preserved Efficacy of Secretoneurin Gene Therapy in Hypercholesterolemia
Introduction: Hypercholesterolemia (HC) is a risk factor for the development of cardiovascular disorders and has been identified to be associated with endothelial dysfunction. Like vascular endothelial growth factor (VEGF) the neuropeptide secretoneurin (SN) is up-regulated by hypoxia and induces angio-, arterio- and vasculogenesis. The aim of this study is to evaluate the efficacy of SN-gene therapy in a condition associated with an impaired vascular response.
Methods/Results: To mimic HC in-vitro endothelial cells were incubated with oxidized LDL (oxLDL). Even in the presence of oxLDL SN significantly stimulated capillary tube formation, proliferation and activation of signaling pathways like ERK1/2 in human umbilical vein endothelial cells and human coronary artery endothelial cells. All observed effects were comparable to VEGF.
To assess the efficacy of SN in-vivo Apo E -/- mice set on western diet for 12 weeks underwent hind limb ischemia (HLI) or experimental myocardial infarction (MI). SN-plasmid (p-SN) or control-plasmid (p-ctr) was injected in the ischemic adductor muscle or the infarct border zone. In the HLI-model SN-therapy increased capillary (capillaries/HPF 200x: p-SN 354.6±14 vs. p-ctr 204.8±8.6; P<0.001) and arteriole (arterioles/HPF 200x: p-SN 5.6±0.5 vs. p-ctr 3.1±0.24; P<0.001) density and significantly improved limb reperfusion. Interestingly, in contrast to C57BL6 mice SN-induced recruitment of endothelial progenitor cells to ischemic sites was drastically abolished in Apo E -/- mice.
In the MI-model SN-therapy resulted in a significant increase of cardiac angiogenesis (1.35-fold, P<0.01) and arteriogenesis (1.5-fold, P<0.05). Moreover, an improvement of cardiac parameters (EF % 49.2±4.3 vs. 34.1±2.8, P<0.01; left ventricular end diastolic diameter mm 3.2±0.2 vs. 3.8±0.3, P<0.05; n=13) was observed. Elevated SN plasma-levels or an influence on the development of atherosclerosis were not detected after local injection of p-SN (% aortic plaque area: p-SN 15.6±0.8 vs. p-ctr 15.2±2, n=5, n.s.; % plaque area aortic-root: p-SN 27.1±1.4 vs. p-ctr 23±3.3, n=5, n.s.).
Conclusion: SN-gene therapy is a safe approach for the treatment of cardiovascular diseases with preserved efficacy in hypercholesterolemia.
Author Disclosures: R. Kirchmair: None. D. Lener: None. W. Schgoer: None. K. Albrecht-Schgoer: None. I. Tancevski: None. W. Franz: None. P. Marschang: None. M. Theurl: None.
- © 2014 by American Heart Association, Inc.