Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts

doi:10.1016/j.athoracsur.2003.10.008

The Annals of Thoracic Surgery

Volume 77, Issue 5, May 2004, Pages 1580-1585

https://doi.org/10.1016/j.athoracsur.2003.10.008 Get rights and content

Abstract

Background

Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. Rapamycin coated stents have been demonstrated to suppress restenosis in experimental and clinical studies of percutaneous coronary catheter intervention. We investigated whether rapamycin can reduce neointima formation in a mouse model of vein graft disease.

Methods

C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. In the treatment group, 100 μg or 200 μg of rapamycin was applied locally in pluronic gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4, and 6 weeks and underwent morphometric analysis as well as immunohistochemical analysis.

Results

In grafted veins without treatment (controls), median intimal thickness was 9.6 (6.4 to 29)μm, 11.9 (7.9 to 39.9)μm, 46.6 (12.4 to 57.7)μm, and 57.5 (32.5 to 71.1)μm after 1, 2, 4, and 6 weeks, respectively. Treatment with 100 μg or 200 μg rapamycin showed a dose dependant reduction of intimal thickness. In the 200 μg rapamycin treatment group the intimal thickness was 4.3 (3.4 to 5.6)μm, 3.8 (3.2 to 6.3)μm, 17.1 (4.8 to 63)μm, and 33.9 (11.3 to 80.3)μm after 1, 2, 4, and 6 weeks, respectively. This difference of intimal thickness of 200 μg treated animals compared with controls was statistically significant at 1 and 2 weeks. Immunohistochemically the reduction of intimal thickness was associated with a decreased amount of infiltration of CD-8 positive cells and a decreased amount of metallothionein positive cells in the rapamycin treated grafts.

Conclusions

We conclude that perivascular application of rapamycin inhibits neointimal hyperplasia of vein grafts in a mouse model. These results suggest that rapamycin may have a therapeutic potential for the treatment of vein graft disease.

Section snippets

Mice and vein grafting

Three month-old male C57BL/6J mice were purchased from Harlan-Winkelmann (Borchen, Germany). They were maintained at 24°C and received food and water ad libitum. All procedures were performed according to protocols approved by the Austrian Ministry of Science according to Section 8 of the law on animal experiments and all animals were treated according to the Guide for the Use and Care of Laboratory Animals, published by the National Institutes of Health (National Institutes of Health

Results

The median intimal thickness in native veins was 1.6 (1.3 to 2.4)μm. Neointimal hyperplasia developed in all vein grafts (Fig 1). In grafted veins without treatment (controls, n = 6 or 7 at each point of time) median intimal thickness was 9.6 (6.4 to 29)μm, 11.9 (7.9 to 39.9)μm, 46.6 (12.4 to 57.7)μm, and 57.5 (32.5 to 71.1)μm after 1, 2, 4, and 6 weeks, respectively. Veins treated with 100 μg rapamycin (n = 6 or 7 at each point of time) showed a trend towards reduction of intimal thickness

Comment

In our study we investigated the effect of perivascularly applied rapamycin on the development of neointimal hyperplasia in experimental vein grafts. We chose rapamycin to test the effect of its antiproliferative properties and of local immunosuppression on the pathogenesis of vein graft disease. Hirko and colleagues [22] demonstrated a reduced intimal thickness and decreased inflammatory cell infiltration in canine vein grafts after orally applied cyclosporine therapy.

With the use of pluronic

Conclusion

We conclude that perivascular application of rapamycin substantially inhibits neointimal hyperplasia of vein grafts in a mouse model. This reduction of vein graft disease is associated with a decreased amount of infiltration of CD-8 positive cells and a decreased amount of metallothionein in the rapamycin treated grafts. These results suggest that rapamycin may have a therapeutic potential for the treatment of vein graft disease.

Acknowledgements

This work was, in part, supported by a grant from the Fund for Research Development at Innsbruck University Hospital and from SKWB Schoeller Bank.

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Original article: cardiovascularLocal application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts

Abstract

Background

Methods

Results

Conclusions

Section snippets

Mice and vein grafting

Results

Comment

Conclusion

Acknowledgements

J Am Coll Cardiol

Atherosclerosis

Lab Invest

Clin Biochem

Transplant Proc

Transplant Proc

Transplant Proc

Transplant Proc

Am J Pathol

J Vasc Surg

J Thorac Cardiovasc Surg

Cardiovasc Surg

Curr Opin Chem Biol

Tissue Cell

J Mol Cell Cardiol

Aortocoronary saphenous vein graft disease

Circulation

The intima soil for atherosclerosis and restenosis

Circ Res

The development of rapamycin and its application to stent restenosis

Circulation

Original article: cardiovascular
Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts