Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice
Target substrate-specific hammerhead ribozyme cleaves the specific mRNA efficiently and results in the inhibition of gene expression. In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. The goal of this study is to demonstrate that l...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116301858 |
| _version_ | 1828374880402276352 |
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| author | Hersharan Nischal Hua Sun Yuchun Wang David A Ford Ying Cao Peng Wei Ba-Bie Teng |
| author_facet | Hersharan Nischal Hua Sun Yuchun Wang David A Ford Ying Cao Peng Wei Ba-Bie Teng |
| author_sort | Hersharan Nischal |
| collection | DOAJ |
| description | Target substrate-specific hammerhead ribozyme cleaves the specific mRNA efficiently and results in the inhibition of gene expression. In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. The goal of this study is to demonstrate that long-term reduction of apoB gene expression using hammerhead ribozyme would result in inhibition of atherosclerosis development. We designed two hammerhead ribozymes targeted at the nucleotides of apoB mRNA GUC2326 (designated RB1) and GUA6679 (designated RB15), and we used self-complementary adeno-associated virus 8.2 (scAAV8.2) vector to deliver these active ribozymes of RB1, RB15, combination of RB1/RB15, and an inactive hammerhead ribozyme RB15 mutant to atherosclerosis-prone LDb mice (Ldlr−/−Apobec1−/−). LDb mice lack both low density lipoproteins (LDL) receptor (Ldlr−/−) and apoB mRNA editing enzyme (Apobec1−/−) genes and develop atherosclerosis spontaneously. After the RB1, RB15, or combination of RB1/RB15 ribozymes treatment, the LDb mice had significantly decreased plasma triglyceride and apoB levels, resulting in markedly decreased of atherosclerotic lesions, Furthermore, the active ribozymes treatment decreased the levels of diacylglycerol acyltransferase 1 (Dgat1) mRNA and the levels of multiple diacylglycerol (DAG) molecular species. These results provide the first evidence that decreased apoB levels results to reduction of Dgat1 expression and triglyceride levels (TAG), which had a significant impact on the development of atherosclerosis. |
| first_indexed | 2024-04-14T07:39:34Z |
| format | Article |
| id | doaj.art-7aa883cda6d240209525749710b614fa |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-14T07:39:34Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-7aa883cda6d240209525749710b614fa2022-12-22T02:05:33ZengElsevierMolecular Therapy: Nucleic Acids2162-25312013-01-012C10.1038/mtna.2013.53Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in MiceHersharan Nischal0Hua Sun1Yuchun Wang2David A Ford3Ying Cao4Peng Wei5Ba-Bie Teng6Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center, Houston, Texas, USACenter for Human Genetics, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center, Houston, Texas, USACenter for Human Genetics, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center, Houston, Texas, USADepartment of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, St Louis, Missouri, USADivision of Biostatistics and Human Genetics Center, School of Public Health, the University of Texas Health Science Center, Houston, Texas, USADivision of Biostatistics and Human Genetics Center, School of Public Health, the University of Texas Health Science Center, Houston, Texas, USACenter for Human Genetics, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center, Houston, Texas, USATarget substrate-specific hammerhead ribozyme cleaves the specific mRNA efficiently and results in the inhibition of gene expression. In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. The goal of this study is to demonstrate that long-term reduction of apoB gene expression using hammerhead ribozyme would result in inhibition of atherosclerosis development. We designed two hammerhead ribozymes targeted at the nucleotides of apoB mRNA GUC2326 (designated RB1) and GUA6679 (designated RB15), and we used self-complementary adeno-associated virus 8.2 (scAAV8.2) vector to deliver these active ribozymes of RB1, RB15, combination of RB1/RB15, and an inactive hammerhead ribozyme RB15 mutant to atherosclerosis-prone LDb mice (Ldlr−/−Apobec1−/−). LDb mice lack both low density lipoproteins (LDL) receptor (Ldlr−/−) and apoB mRNA editing enzyme (Apobec1−/−) genes and develop atherosclerosis spontaneously. After the RB1, RB15, or combination of RB1/RB15 ribozymes treatment, the LDb mice had significantly decreased plasma triglyceride and apoB levels, resulting in markedly decreased of atherosclerotic lesions, Furthermore, the active ribozymes treatment decreased the levels of diacylglycerol acyltransferase 1 (Dgat1) mRNA and the levels of multiple diacylglycerol (DAG) molecular species. These results provide the first evidence that decreased apoB levels results to reduction of Dgat1 expression and triglyceride levels (TAG), which had a significant impact on the development of atherosclerosis.http://www.sciencedirect.com/science/article/pii/S2162253116301858AAVapolipoprotein Batherosclerosisdiacylglycerolribozymes |
| spellingShingle | Hersharan Nischal Hua Sun Yuchun Wang David A Ford Ying Cao Peng Wei Ba-Bie Teng Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice Molecular Therapy: Nucleic Acids AAV apolipoprotein B atherosclerosis diacylglycerol ribozymes |
| title | Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice |
| title_full | Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice |
| title_fullStr | Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice |
| title_full_unstemmed | Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice |
| title_short | Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice |
| title_sort | long term expression of apolipoprotein b mrna specific hammerhead ribozyme via scaav8 2 vector inhibits atherosclerosis in mice |
| topic | AAV apolipoprotein B atherosclerosis diacylglycerol ribozymes |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116301858 |
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