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Updated: Jul 18, 2026
Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy
Published on: December 4, 2010
Antisense ERK1/2 oligodeoxynucleotide gene therapy attenuates graft arteriosclerosis of aortic transplant in a rat
Unlabelled:
Chronic rejection is a major cause of transplant loss that is effected by the extracellular signal-regulated kinases (ERK) pathway. This study investigated the effects of antisense ERK1/2 oligodeoxynucleotide(ODN) gene therapy on chronic rejection.
Methods:
Lewis (RT1(1)) rats served as recipients of Brown-Norway (BN, RT1n) grafts. The BN rat abdominal aortas were harvested and orthotopically grafted into Lewis rats. The recipients were divided into three groups: (1) control group (n = 9), (2) random ODN transfer group (n = 10), and (3) antisense ODN transfer group (n = 10). At day 60 after transplantation, the recipients were sacrificed; the grafted aortas were evaluated histologically and immunohistochemically. ERK1/2 protein expression in the grafts was determined using Western Blot assays. Serum levels of slCAM-1 were detected by ELISA.
Results:
In the control group and random ODN transfer group, we observed a remarkable degree of intimal hyperplasia and inflammatory cell infiltration, including macrophages and T cells. Compared with the control group, antisense ERK1/2 ODN gene therapy resulted in a significant reduction in neointimal proliferation (P < .01), inhibition of ERK1/2 protein expression (P < .01), decreased graft infiltration with CD4+ T lymphocytes (P < .01), CD8+ T lymphocytes(P < .05), and ED-1 macrophages (P < .01) with decreased serum levels of sICAM-1 (P < .05). We obtained a negative correlation between ERK1/2 expression and immune cell infiltration or ICAM-1 level.
Conclusions:
Antisense ERK1/2 gene therapy can attenuate graft arteriosclerosis so as to protect aortic allografts. The protection seemed to correlate with inhibition of inflammatory infiltration, implying that the ERK1/2 signal transduction pathway plays an important role in the process of chronic vascular rejection.
Insights
Antisense ERK1/2 gene therapy significantly reduced chronic vascular rejection in aortic allografts by inhibiting inflammation and intimal hyperplasia. This highlights the ERK1/2 pathway's role in transplant rejection.
Area of Science:
- Transplantation immunology
- Molecular biology
- Vascular biology
Background:
- Chronic rejection is a primary cause of transplant failure.
- The extracellular signal-regulated kinases (ERK) pathway is implicated in chronic rejection.
- Investigating therapeutic targets for chronic rejection is crucial for improving transplant outcomes.
Purpose of the Study:
- To evaluate the efficacy of antisense ERK1/2 oligodeoxynucleotide (ODN) gene therapy in mitigating chronic rejection of aortic allografts.
- To determine the impact of this gene therapy on key markers of rejection, including intimal hyperplasia and immune cell infiltration.
Main Methods:
- Lewis rats received Brown-Norway rat aortic grafts.
- Recipients were divided into control, random ODN, and antisense ODN groups.
- Grafts were analyzed histologically and immunohistochemically; ERK1/2 expression and serum sICAM-1 levels were quantified.
Main Results:
- Antisense ERK1/2 ODN therapy significantly reduced neointimal proliferation and ERK1/2 protein expression in grafts.
- Gene therapy decreased infiltration of CD4+, CD8+ T lymphocytes, and macrophages.
- Reduced serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) were observed, correlating negatively with ERK1/2 expression.
Conclusions:
- Antisense ERK1/2 gene therapy effectively attenuates graft arteriosclerosis and protects aortic allografts.
- The protective effect is associated with the inhibition of inflammatory cell infiltration.
- The ERK1/2 signal transduction pathway is a critical mediator in chronic vascular rejection.
