Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the infarcted myocardium of type 1 diabetic rats.
OBJECTIVE
Hyperglycemia impairs angiogenesis in response to ischemia, leading to ventricular remodeling. Although the effects of overexpressing angiogenic growth factors have been studied in inducing angiogenesis, the formation of functional vessels remains a challenge. The present study evaluates the reversal of diabetes-mediated impairment of angiogenesis in the infarcted diabetic rat myocardium by proangiogenic gene therapy.


METHODS
Ad*VEGF and Ad*Ang1 were intramyocardially administered in combination immediately after myocardial infarction to nondiabetic and diabetic rats. Ad*LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. The myocardial function was measured by echocardiography 30 days after the intervention.


RESULTS
We observed reduced fibrosis and increased capillary/arteriolar density along with reduced ventricular remodeling, as assessed by echocardiography in the treated diabetic animals compared with the nontreated diabetic controls. We also observed increased phosphorylated mitogen-activated protein kinase-activated protein kinase-2, 2 days after the treatment and increased expression of vascular endothelial growth factor (VEGF), Flk-1, angiopoietin-1 (Ang-1), Tie-2, and survivin, 4 days after treatment in the diabetic animals. Gel shift analysis revealed that the combination gene therapy stimulated the DNA binding activity of nuclear factor-kappaB in the diabetic animals.


CONCLUSIONS
Our preclinical data demonstrate the efficacy of coadministration of adenoviral VEGF and Ang-1 in increasing angiogenesis and reducing ventricular remodeling in the infarcted diabetic myocardium. These unique results call for the initiation of a clinical trial to assess the efficacy of this therapeutic strategy in the treatment of diabetes-related human heart failure.
Samuel
Samson Mathews
SM
Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA.
Akita
Yuzo
Y
Paul
Debayon
D
Thirunavukkarasu
Mahesh
M
Zhan
Lijun
L
Sudhakaran
Perumana R
PR
Li
Chuanfu
C
Maulik
Nilanjana
N
D000256:Adenoviridae; D042683:Angiopoietin-1 / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology*; D000818:Animals; D002196:Capillaries / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics; D009203:Myocardial Infarction / Q000503:physiopathology*; D051381:Rats; D042787:Receptor, TIE-2 / Q000187:drug effects / Q000235:genetics; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
D042683:Angiopoietin-1; C516989:Birc5 protein, rat; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2