| First Author | Kumar S | Year | 2017 |
| Journal | Lab Invest | Volume | 97 |
| Issue | 8 | Pages | 935-945 |
| PubMed ID | 28504688 | Mgi Jnum | J:312651 |
| Mgi Id | MGI:6791801 | Doi | 10.1038/labinvest.2017.47 |
| Citation | Kumar S, et al. (2017) Accelerated atherosclerosis development in C57Bl6 mice by overexpressing AAV-mediated PCSK9 and partial carotid ligation. Lab Invest 97(8):935-945 |
| abstractText | Studying the role of a particular gene in atherosclerosis typically requires a time-consuming and often difficult process of generating double knockouts or transgenics on ApoE(-/-) or LDL receptor (LDLR)(-/-) background. Recently, it was reported that adeno-associated-virus-8 (AAV8)-mediated overexpression of PCSK9 (AAV8-PCSK9) rapidly induced hyperlipidemia. However, using this method in C57BL6 wild-type (C57) mice, it took ~3 months to develop atherosclerosis. Our partial carotid ligation model is used to rapidly develop atherosclerosis by inducing disturbed flow in the left common carotid artery within 2 weeks in ApoE(-/-) or LDLR(-/-) mice. Here, we combined these two approaches to develop an accelerated model of atherosclerosis in C57 mice. C57 mice were injected with AAV9-PCSK9 or AAV9-luciferase (control) and high-fat diet was initiated. A week later, partial ligation was performed. Compared to the control, AAV-PCSK9 led to elevated serum PCSK9, hypercholesterolemia, and rapid atherosclerosis development within 3 weeks as determined by gross plaque imaging, and staining with Oil-Red-O, Movat's pentachrome, and CD45 antibody. These plaque lesions were comparable to the atherosclerotic lesions that have been previously observed in ApoE(-/-) or LDLR(-/-) mice that were subjected to partial carotid ligation and high-fat diet. Next, we tested whether our method can be utilized to rapidly determine the role of a particular gene in atherosclerosis. Using eNOS(-/-) and NOX1(-/y) mice on C57 background, we found that the eNOS(-/-) mice developed more advanced lesions, while the NOX1(-/y) mice developed less atherosclerotic lesions as compared to the C57 controls. These results are consistent with the previous findings using double knockouts (eNOS(-/-)_ApoE(-/-) and NOX1(-/y)_ApoE(-/-)). AAV9-PCSK9 injection followed by partial carotid ligation is an effective and time-saving approach to rapidly induce atherosclerosis. This accelerated model is well-suited to quickly determine the role of gene(s) interest without generating double or triple knockouts. |
