Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis
Coronary artery venous bypass grafts typically fail because of atherosclerosis driven by lipid and macrophage accumulation. Therapy for vein-graft atherosclerosis is limited to statin drugs, which are only modestly effective. We hypothesized that transduction of vein-graft endothelium of fat-fed rab...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S232905012300133X |
| _version_ | 1797693872295378944 |
|---|---|
| author | Lianxiang Bi Bradley K. Wacker Kaushik Komandur Nicole Sanford David A. Dichek |
| author_facet | Lianxiang Bi Bradley K. Wacker Kaushik Komandur Nicole Sanford David A. Dichek |
| author_sort | Lianxiang Bi |
| collection | DOAJ |
| description | Coronary artery venous bypass grafts typically fail because of atherosclerosis driven by lipid and macrophage accumulation. Therapy for vein-graft atherosclerosis is limited to statin drugs, which are only modestly effective. We hypothesized that transduction of vein-graft endothelium of fat-fed rabbits with a helper-dependent adenovirus expressing apolipoprotein AI (HDAdApoAI) would reduce lipid and macrophage accumulation. Fat-fed rabbits received bilateral external jugular vein-to-carotid artery interposition grafts. Four weeks later, one graft per rabbit (n = 23 rabbits) was infused with HDAdApoAI and the contralateral graft with HDAdNull. Grafts were harvested 12 weeks later. Paired analyses of grafts were performed, with vein graft cholesterol, intimal lipid, and macrophage content as the primary endpoints. HDAd genomes were detected in all grafts. APOAI mRNA was median 63-fold higher in HDAdApoAI grafts versus HDAdNull grafts (p < 0.001). HDAdApoAI grafts had a mean 15% lower total cholesterol (by mass spectrometry; p = 0.003); mean 19% lower intimal lipid (by oil red O staining; p = 0.02); and mean 13% lower expression of the macrophage marker CD68 (by reverse transcriptase-mediated quantitative PCR; p = 0.008). In vivo transduction of vein-graft endothelium achieves persistent APOAI expression and reduces vein-graft cholesterol, intimal lipid, and CD68 expression. Vascular gene therapy with APOAI has promise for preventing vein-graft failure caused by atherosclerosis. |
| first_indexed | 2024-03-12T02:49:52Z |
| format | Article |
| id | doaj.art-0bb220201f12424e87cc8fd11799d3dc |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-12T02:49:52Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-0bb220201f12424e87cc8fd11799d3dc2023-09-04T04:10:22ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-09-0130558572Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosisLianxiang Bi0Bradley K. Wacker1Kaushik Komandur2Nicole Sanford3David A. Dichek4Department of Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USADepartment of Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USADepartment of Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USADepartment of Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USADepartment of Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA; Corresponding author: David A. Dichek, Department of Medicine, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA.Coronary artery venous bypass grafts typically fail because of atherosclerosis driven by lipid and macrophage accumulation. Therapy for vein-graft atherosclerosis is limited to statin drugs, which are only modestly effective. We hypothesized that transduction of vein-graft endothelium of fat-fed rabbits with a helper-dependent adenovirus expressing apolipoprotein AI (HDAdApoAI) would reduce lipid and macrophage accumulation. Fat-fed rabbits received bilateral external jugular vein-to-carotid artery interposition grafts. Four weeks later, one graft per rabbit (n = 23 rabbits) was infused with HDAdApoAI and the contralateral graft with HDAdNull. Grafts were harvested 12 weeks later. Paired analyses of grafts were performed, with vein graft cholesterol, intimal lipid, and macrophage content as the primary endpoints. HDAd genomes were detected in all grafts. APOAI mRNA was median 63-fold higher in HDAdApoAI grafts versus HDAdNull grafts (p < 0.001). HDAdApoAI grafts had a mean 15% lower total cholesterol (by mass spectrometry; p = 0.003); mean 19% lower intimal lipid (by oil red O staining; p = 0.02); and mean 13% lower expression of the macrophage marker CD68 (by reverse transcriptase-mediated quantitative PCR; p = 0.008). In vivo transduction of vein-graft endothelium achieves persistent APOAI expression and reduces vein-graft cholesterol, intimal lipid, and CD68 expression. Vascular gene therapy with APOAI has promise for preventing vein-graft failure caused by atherosclerosis.http://www.sciencedirect.com/science/article/pii/S232905012300133Xadenovirusapolipoprotein AIatherosclerosiscarotid arterycholesterolgene therapy |
| spellingShingle | Lianxiang Bi Bradley K. Wacker Kaushik Komandur Nicole Sanford David A. Dichek Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis Molecular Therapy: Methods & Clinical Development adenovirus apolipoprotein AI atherosclerosis carotid artery cholesterol gene therapy |
| title | Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis |
| title_full | Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis |
| title_fullStr | Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis |
| title_full_unstemmed | Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis |
| title_short | Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis |
| title_sort | apolipoprotein a i vascular gene therapy reduces vein graft atherosclerosis |
| topic | adenovirus apolipoprotein AI atherosclerosis carotid artery cholesterol gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S232905012300133X |
| work_keys_str_mv | AT lianxiangbi apolipoproteinaivasculargenetherapyreducesveingraftatherosclerosis AT bradleykwacker apolipoproteinaivasculargenetherapyreducesveingraftatherosclerosis AT kaushikkomandur apolipoproteinaivasculargenetherapyreducesveingraftatherosclerosis AT nicolesanford apolipoproteinaivasculargenetherapyreducesveingraftatherosclerosis AT davidadichek apolipoproteinaivasculargenetherapyreducesveingraftatherosclerosis |