Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice
Adeno-associated virus (AAV) is the most widely utilized vector for gene therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9), predominantly expressed in the liver, plays a crucial role in lipid regulation and atherosclerosis progression. Here, we developed a novel chimeric AAV8.P-PCSK9 sh...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124002067 |
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| author | Xiaocui Chen Minghui Sun Xiang Ma Yitong Ma Bangdang Chen |
| author_facet | Xiaocui Chen Minghui Sun Xiang Ma Yitong Ma Bangdang Chen |
| author_sort | Xiaocui Chen |
| collection | DOAJ |
| description | Adeno-associated virus (AAV) is the most widely utilized vector for gene therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9), predominantly expressed in the liver, plays a crucial role in lipid regulation and atherosclerosis progression. Here, we developed a novel chimeric AAV8.P-PCSK9 short hairpin RNA (shRNA) vector that incorporates a cross-species specific shRNA targeting PCSK9 to assess its effects on lipid levels and atherosclerosis in mice. AAV8.P demonstrated superior transduction efficiency and safety, achieving about 90% liver transduction and maintaining transgene expression for up to a year. The AAV8.P-PCSK9 shRNA exhibited typical liver-tropism and effectively silenced hepatic PCSK9. Moreover, it significantly lowered serum cholesterol and triglyceride levels while increasing LDL-R level without causing hepatotoxicity in wild-type mice. Additionally, it decreased PCSK9 expression and elevated low-density lipoprotein receptor expression in Apolipoprotein E-deficient mice, leading to early changes in lipid profiles but lacking a sustained impact on circulating lipids. Importantly, silencing PCSK9 resulted in reduced plaque areas with enhanced stability, decreased inflammatory macrophage infiltration, and lower levels of vascular and systemic inflammatory markers. These findings indicate that targeted silencing of hepatic PCSK9 significantly reduces lipid levels and effectively mitigates atherosclerosis progression by inhibiting inflammatory responses via the AAV8.P-PCSK9 shRNA vector, thereby providing critical support for its clinical translation. |
| format | Article |
| id | doaj-art-83b948de9646418fbf4b3a3da6f96c8e |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-83b948de9646418fbf4b3a3da6f96c8e2025-01-18T05:04:46ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-03-01331101390Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− miceXiaocui Chen0Minghui Sun1Xiang Ma2Yitong Ma3Bangdang Chen4Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China; Basic Medical College, Xinjiang Medical University, Urumqi 830011, P.R. ChinaDepartment of Nephrology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, P.R. ChinaXinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China; Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. ChinaXinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China; Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. ChinaXinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P.R. China; Basic Medical College, Xinjiang Medical University, Urumqi 830011, P.R. China; Corresponding author: Bangdang Chen, Clinical Medical Research Institute of Xinjiang Medical University, 137 Liyushan South Road, Urumqi 830054, P.R. China.Adeno-associated virus (AAV) is the most widely utilized vector for gene therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9), predominantly expressed in the liver, plays a crucial role in lipid regulation and atherosclerosis progression. Here, we developed a novel chimeric AAV8.P-PCSK9 short hairpin RNA (shRNA) vector that incorporates a cross-species specific shRNA targeting PCSK9 to assess its effects on lipid levels and atherosclerosis in mice. AAV8.P demonstrated superior transduction efficiency and safety, achieving about 90% liver transduction and maintaining transgene expression for up to a year. The AAV8.P-PCSK9 shRNA exhibited typical liver-tropism and effectively silenced hepatic PCSK9. Moreover, it significantly lowered serum cholesterol and triglyceride levels while increasing LDL-R level without causing hepatotoxicity in wild-type mice. Additionally, it decreased PCSK9 expression and elevated low-density lipoprotein receptor expression in Apolipoprotein E-deficient mice, leading to early changes in lipid profiles but lacking a sustained impact on circulating lipids. Importantly, silencing PCSK9 resulted in reduced plaque areas with enhanced stability, decreased inflammatory macrophage infiltration, and lower levels of vascular and systemic inflammatory markers. These findings indicate that targeted silencing of hepatic PCSK9 significantly reduces lipid levels and effectively mitigates atherosclerosis progression by inhibiting inflammatory responses via the AAV8.P-PCSK9 shRNA vector, thereby providing critical support for its clinical translation.http://www.sciencedirect.com/science/article/pii/S2329050124002067proprotein convertase subtilisin/kexin type 9adeno-associated virusgene therapyatherosclerosisinflammation |
| spellingShingle | Xiaocui Chen Minghui Sun Xiang Ma Yitong Ma Bangdang Chen Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice Molecular Therapy: Methods & Clinical Development proprotein convertase subtilisin/kexin type 9 adeno-associated virus gene therapy atherosclerosis inflammation |
| title | Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice |
| title_full | Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice |
| title_fullStr | Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice |
| title_full_unstemmed | Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice |
| title_short | Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE−/− mice |
| title_sort | silencing hepatic pcsk9 via novel chimeric aav8 mitigates the progression of atherosclerosis by inhibiting inflammation in apoe mice |
| topic | proprotein convertase subtilisin/kexin type 9 adeno-associated virus gene therapy atherosclerosis inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124002067 |
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