Secretoneurin gene therapy improves hind limb and cardiac ischaemia in Apo E⁻/⁻ mice without influencing systemic atherosclerosis.
OBJECTIVE
Hypercholesterolaemia is a major risk factor for cardiovascular diseases and has been shown to influence angiogenesis in the hind limb ischaemia (HLI) model. The impaired up-regulation of angiogenic factors seems to be one of the underlying mechanisms for reduced vessel formation. Since we found that secretoneurin (SN) is up-regulated in hypoxic skeletal muscle cells and exerts beneficial effects in myocardial and HLI, we hypothesized that SN therapy might improve neovascularization in hypercholesterolaemic Apo E(-/-) (Apo E knockout) mice suffering from an impaired vascular response.


RESULTS
For in vitro experiments, endothelial cells (ECs) were incubated with oxidized low-density lipoprotein (oxLDL) to mimic hypercholesterolaemia. EC function was impaired by oxLDL, but SN induced EC proliferation and in vitro tube formation under these conditions. In the HLI model, injection of SN plasmid resulted in a significant better outcome regarding blood flow recovery, amputation rate, and vessel density. In the myocardial infarction (MI) model, the SN group showed improvement in cardiac parameters. Aortic plaque area was not influenced by local SN injection. Interestingly, SN-induced recruitment of angiogenic monocytic cells was abolished under hypercholesterolaemia.


CONCLUSIONS
SN gene therapy exerts beneficial effects in cardiovascular animal models in Apo E(-/-) mice without influencing atherosclerosis and might qualify as a promising therapy for cardiovascular disorders.
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria markus.theurl@i-med.ac.at rudolf.kirchmair@i-med.ac.at.
Markus
M
Theurl
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria.
Wilfried
W
Schgoer
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria.
Karin
K
Albrecht-Schgoer
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria.
Daniela
D
Lener
Medical Clinic 3, Oncology, Hematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany Department of Haematology and Oncology, Medical University of Innsbruck, University Hospital of Internal Medicine V, Innsbruck, Austria.
Dominik
D
Wolf
Department of Haematology and Oncology, Medical University of Innsbruck, University Hospital of Internal Medicine V, Innsbruck, Austria.
Maria
M
Wolf
Department of Clinically Immunology and Infectious Diseases, Medical University of Innsbruck, University Hospital of Internal Medicine VI, Innsbruck, Austria.
Egon
E
Demetz
Department of Clinically Immunology and Infectious Diseases, Medical University of Innsbruck, University Hospital of Internal Medicine VI, Innsbruck, Austria.
Piotr
P
Tymoszuk
Department of Clinically Immunology and Infectious Diseases, Medical University of Innsbruck, University Hospital of Internal Medicine VI, Innsbruck, Austria.
Ivan
I
Tancevski
Medical University of Innsbruck, Institute of Pharmacology, Innsbruck, Austria.
Reiner
R
Fischer-Colbrie
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria.
Wolfgang-Michael
WM
Franz
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria.
Peter
P
Marschang
Department of Cardiology and Angiology, Medical University of Innsbruck, University Hospital of Internal Medicine III, Anichstraße 35, Innsbruck A-6020, Austria markus.theurl@i-med.ac.at rudolf.kirchmair@i-med.ac.at.
Rudolf
R
Kirchmair
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use*; D053381:Secretogranin II / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use*
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D009479:Neuropeptides; D053381:Secretogranin II; C099252:oxidized low density lipoprotein; C081159:secretoneurin
Hind limb ischaemia; Hypercholesterolaemia; Myocardial infarction; Neuropeptides; Therapeutic angiogenesis