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

Samson Mathews Samuel, Yuzo Akita, Debayon Paul, Mahesh Thirunavukkarasu, Lijun Zhan, Perumana R. Sudhakaran, Chuanfu Li, Nilanjana Maulik

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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. RESEARCH DESIGN AND 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-κB 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.

Original languageEnglish
Pages (from-to)51-60
Number of pages10
JournalDiabetes
Volume59
Issue number1
DOIs
Publication statusPublished - 1 Jan 2010
Externally publishedYes

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Angiopoietin-1
Ventricular Remodeling
Vascular Endothelial Growth Factor A
Myocardium
Genetic Therapy
Echocardiography
Angiogenesis Inducing Agents
Electrophoretic Mobility Shift Assay
Therapeutics
Mitogen-Activated Protein Kinases
Hyperglycemia
Protein Kinases
Intercellular Signaling Peptides and Proteins
Fibrosis
Research Design
Ischemia
Heart Failure
Myocardial Infarction
Clinical Trials
Control Groups

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Mathews Samuel, Samson; Akita, Yuzo; Paul, Debayon; Thirunavukkarasu, Mahesh; Zhan, Lijun; Sudhakaran, Perumana R.; Li, Chuanfu; Maulik, Nilanjana.

In: Diabetes, Vol. 59, No. 1, 01.01.2010, p. 51-60.

Research output: Contribution to journalArticle

Mathews Samuel, Samson ; Akita, Yuzo ; Paul, Debayon ; Thirunavukkarasu, Mahesh ; Zhan, Lijun ; Sudhakaran, Perumana R. ; Li, Chuanfu ; Maulik, Nilanjana. / 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. In: Diabetes. 2010 ; Vol. 59, No. 1. pp. 51-60.
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T1 - 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

AU - Mathews Samuel, Samson

AU - Akita, Yuzo

AU - Paul, Debayon

AU - Thirunavukkarasu, Mahesh

AU - Zhan, Lijun

AU - Sudhakaran, Perumana R.

AU - Li, Chuanfu

AU - Maulik, Nilanjana

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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. RESEARCH DESIGN AND 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-κB 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.

AB - 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. RESEARCH DESIGN AND 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-κB 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.

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