Adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 gene therapy inhibits activation of vascular smooth muscle cells and angiogenesis, and ameliorates transplant arteriosclerosis.

Abstract

UNLABELLED:

The aim of this study was to explore underlying mechanisms of transplant arteriosclerosis (TA) based on intimal thickening that involve activation of vascular smooth muscle cells (VSMCs) and angiogenesis. We also examined the effects of adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 (ERK2) (Adanti-ERK2) gene therapy on TA.

METHODS:

We employed a rat aorta transplantation model (Brown-Norway → Lewis). The animals were divided into: (1) an isograft group (n = 6), (2) an empty control group (n = 6), (3) the Ad-LacZ group (n = 6), and (4) the adanti-ERK2 group (n = 6). At 60 days after transplantation, we documented the ratio of intima/(intima + media) the isografts pathologically. Staining for α-actin and platelet-derived growth factor (PDGF)-BB was performed to analyze the migration and secretion of VSMCs. We evaluated angiogenesis and COX-2 staining.

RESULT:

Isografts showed normal histology; allografts from the empty control group and the Ad-LacZ group displayed typical TA lesions, while the pathology was significantly improved among the adanti-ERK2 group. The ratios of intima/(intima + media) were 7.6 ± 2.1%, 81.4% ± 6.7%, 85.9% ± 9.4%, and 15.9% ± 4.1% among the isograft group, the empty control, the Ad-LacZ, and the adanti-ERK2 groups respectively. The α-actin+ cells in the intima per field (×400) were 2.1 ± 1.1, 71.3 ± 9.2, 76.4 ± 11.3, and 34.8 ± 5.3, PDGF-BB+ cells, 0.9 ± 0.5, 28.4 ± 3.4, 29.1 ± 3.2, and 8.6 ± 1.7; COX-2+ cells in new capillaries were none, 36.3 ± 8.3, 40.9 ± 9.2, and 10.4 ± 3.9 respectively (P < .05).

CONCLUSION:

Intimal thickening a key feature of TA, involves activation of VSMC (proliferation, migration and secretion), and the accompanying angiogenesis. Adanti-ERK2 gene therapy modulates the mechanisms, protecting allografts against TA.

• Authors: B Zhao, X Li, X Dai, N Gong
• Journal: Transplantation proceedings (Transplant Proc) Vol. 45 Issue 2 Pg. 639-42 (Mar 2013) ISSN: 1873-2623 [Electronic] United States
• PMID: 23498803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• DNA, Antisense
• Proto-Oncogene Proteins c-sis
• Becaplermin
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Mapk1 protein, rat
• Mitogen-Activated Protein Kinase 1

Topics

• Adenoviridae (genetics)
• Animals
• Aorta, Abdominal (enzymology, pathology, transplantation)
• Arteriosclerosis (enzymology, genetics, pathology, prevention & control)
• Becaplermin
• Cell Movement
• Cell Proliferation
• Cyclooxygenase 2 (metabolism)
• DNA, Antisense (genetics, metabolism)
• Genetic Therapy (methods)
• Genetic Vectors
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Muscle, Smooth, Vascular (enzymology, pathology, transplantation)
• Myocytes, Smooth Muscle (enzymology, pathology, transplantation)
• Neointima
• Neovascularization, Pathologic
• Proto-Oncogene Proteins c-sis (metabolism)
• Rats
• Rats, Inbred BN
• Rats, Inbred Lew
• Transduction, Genetic