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Inhibitory effect of wild-type P53 gene transfer on graft coronary artery disease
Li-Ping Wang1, Zhi-Bo Jia2, Yue Liu3
1Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Objective:
The aim of the present study was to investigate the inhibitory effect of wild-type P53 gene transfer on graft coronary artery disease (GCAD) after heart transplantation and the underlying mechanisms.
Methods:
A rat model of heterotopic heart transplantation was established using Wistar rats as donors and Sprague-Dawley (SD) rats as recipients. The donor hearts were collected and perfused, via the coronary artery, with 800 μl of recombinant adenovirus carrying the P53 gene (Ad-P53). Thirty minutes later, heart transplant was performed. At 5 d after the transplant surgery, the expression of the exogenous P53 gene and protein in the coronary artery tissues of the donor hearts was examined. At 28 d after the transplant surgery, tissues were collected from the transplanted hearts. The degree of coronary artery stenosis was examined, and apoptosis of the coronary artery smooth muscle cells in the donor hearts was analysed. In addition, histological changes in the vital organs of the recipient rats and the levels of serum biochemical indicators in the rats were also examined.
Results:
The exogenous gene was successfully transferred into donor heart tissues and the coronary artery and was highly expressed. At 28 d after the transplant surgery, the ratio of tunica intima thickness to tunica media thickness (I/M) and the ratio of wall thickness to the lumen diameter of the coronary artery were decreased in the Ad-P53 group compared to those in the Ad-LacZ group and the control group (P < 0.05). A terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay revealed that the percentage of apoptotic coronary artery smooth muscle cells in the donor hearts was significantly increased in the Ad-P53 group compared to that in the Ad-LacZ group and the control group (P < 0.01). The wild-type P53 gene had no effect on the morphology and functions of the vital organs of the recipient rats.
Conclusions:
P53 gene transfer inhibits coronary artery intimal hyperplasia and reduces the degree of luminal stenosis in transplanted hearts. The inhibitory effect may be related to the wild-type P53 gene-induced apoptosis of vascular smooth muscle cells and inhibition of vascular smooth muscle cell proliferation. This approach is effective and safe and may have good prospects for clinical application.
Insights
Wild-type P53 gene transfer effectively inhibits graft coronary artery disease (GCAD) after heart transplantation by reducing intimal hyperplasia. This approach induces apoptosis in vascular smooth muscle cells, showing promise for clinical application.
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Transplantation Immunology
Background:
- Graft Coronary Artery Disease (GCAD) is a major cause of late graft loss after heart transplantation.
- The underlying mechanisms of GCAD involve intimal hyperplasia and vascular smooth muscle cell proliferation.
- Effective therapeutic strategies to prevent or treat GCAD are urgently needed.
Purpose of the Study:
- To investigate the inhibitory effect of wild-type P53 gene transfer on GCAD.
- To elucidate the mechanisms by which P53 gene transfer impacts GCAD.
- To assess the safety and efficacy of P53 gene therapy in a heart transplantation model.
Main Methods:
- A rat model of heterotopic heart transplantation was established.
- Recombinant adenovirus carrying the P53 gene (Ad-P53) was used for gene transfer into donor hearts.
- Coronary artery stenosis, vascular smooth muscle cell apoptosis, and histological changes were assessed post-transplantation.
Main Results:
- Successful transfer and high expression of the exogenous P53 gene and protein in donor heart coronary arteries.
- Ad-P53 treatment significantly reduced coronary artery intimal thickening and lumen stenosis.
- P53 gene transfer markedly increased apoptosis of coronary artery smooth muscle cells.
Conclusions:
- Wild-type P53 gene transfer effectively inhibits coronary artery intimal hyperplasia in transplanted hearts.
- The mechanism involves P53-induced apoptosis of vascular smooth muscle cells.
- P53 gene therapy is a safe and promising approach for preventing GCAD.
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