Apolipoprotein E-depletion accelerates arterial fat deposition in the spontaneously hypertensive rat
Hypertension and atherosclerosis are often found in one patient causing serious cardiovascular events. An animal model simultaneously expressing hypertension and atherosclerosis would be useful to study such a complex risk status. We therefore attempted to introduce a null mutation of the apolipopro...
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Published in | Experimental Animals Vol. 72; no. 4; pp. 439 - 445 |
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Abstract | Hypertension and atherosclerosis are often found in one patient causing serious cardiovascular events. An animal model simultaneously expressing hypertension and atherosclerosis would be useful to study such a complex risk status. We therefore attempted to introduce a null mutation of the apolipoprotein E (ApoE) gene into the spontaneously hypertensive rat (SHR) using CRISPR/Cas9 to establish a genetic model for atherosclerosis with hypertension. We successfully established SHRApoE(−/−) having a 13-bps deletion in the 5′-end of ApoE gene. Deletion of ApoE protein was confirmed by Western blotting. Blood pressure of SHRApoE(−/−) was comparable to that of SHR. Feeding the rats with high fat high cholesterol diet (HFD) caused a significant increase in LDL cholesterol as well as in triglyceride in SHRApoE(−/−). After 8 weeks of HFD loading, superficial fat deposition was observed both in the aorta and the mesenteric arteries of SHRApoE(−/−) instead of mature atheromatous lesions found in humans. In addition, a null mutation of peroxiredoxin 2 (Prdx2) was introduced into SHRApoE(−/−) to examine the effect of increased oxidative stress on the development of atherosclerosis. SHR with the double depletion of ApoE and Prdx2 did not show mature atheroma either. Further, salt loading did not promote development of atheroma although it accelerated the development of fat deposition. These results indicated that when compared with ApoE-knockout mice, SHRApoE(−/−) was more resistant to atherosclerosis even though they have severe hypertension. |
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AbstractList | Hypertension and atherosclerosis are often found in one patient causing serious cardiovascular events. An animal model simultaneously expressing hypertension and atherosclerosis would be useful to study such a complex risk status. We therefore attempted to introduce a null mutation of the apolipoprotein E (ApoE) gene into the spontaneously hypertensive rat (SHR) using CRISPR/Cas9 to establish a genetic model for atherosclerosis with hypertension. We successfully established SHR
having a 13-bps deletion in the 5'-end of ApoE gene. Deletion of ApoE protein was confirmed by Western blotting. Blood pressure of SHR
was comparable to that of SHR. Feeding the rats with high fat high cholesterol diet (HFD) caused a significant increase in LDL cholesterol as well as in triglyceride in SHR
. After 8 weeks of HFD loading, superficial fat deposition was observed both in the aorta and the mesenteric arteries of SHR
instead of mature atheromatous lesions found in humans. In addition, a null mutation of peroxiredoxin 2 (Prdx2) was introduced into SHR
to examine the effect of increased oxidative stress on the development of atherosclerosis. SHR with the double depletion of ApoE and Prdx2 did not show mature atheroma either. Further, salt loading did not promote development of atheroma although it accelerated the development of fat deposition. These results indicated that when compared with ApoE-knockout mice, SHR
was more resistant to atherosclerosis even though they have severe hypertension. Hypertension and atherosclerosis are often found in one patient causing serious cardiovascular events. An animal model simultaneously expressing hypertension and atherosclerosis would be useful to study such a complex risk status. We therefore attempted to introduce a null mutation of the apolipoprotein E (ApoE) gene into the spontaneously hypertensive rat (SHR) using CRISPR/Cas9 to establish a genetic model for atherosclerosis with hypertension. We successfully established SHRApoE(−/−) having a 13-bps deletion in the 5′-end of ApoE gene. Deletion of ApoE protein was confirmed by Western blotting. Blood pressure of SHRApoE(−/−) was comparable to that of SHR. Feeding the rats with high fat high cholesterol diet (HFD) caused a significant increase in LDL cholesterol as well as in triglyceride in SHRApoE(−/−). After 8 weeks of HFD loading, superficial fat deposition was observed both in the aorta and the mesenteric arteries of SHRApoE(−/−) instead of mature atheromatous lesions found in humans. In addition, a null mutation of peroxiredoxin 2 (Prdx2) was introduced into SHRApoE(−/−) to examine the effect of increased oxidative stress on the development of atherosclerosis. SHR with the double depletion of ApoE and Prdx2 did not show mature atheroma either. Further, salt loading did not promote development of atheroma although it accelerated the development of fat deposition. These results indicated that when compared with ApoE-knockout mice, SHRApoE(−/−) was more resistant to atherosclerosis even though they have severe hypertension. |
ArticleNumber | 23-0012 |
Author | Kaneko, Takehito Nabika, Toru Kawakami, Kohei Mashimo, Tomoji Yamada, Takaya Ohara, Hiroki Matsuo, Hiroyuki |
Author_xml | – sequence: 1 fullname: Matsuo, Hiroyuki organization: Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan – sequence: 2 fullname: Kawakami, Kohei organization: Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan – sequence: 3 fullname: Ohara, Hiroki organization: Department of Functional Pathology, Shimane University Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan – sequence: 4 fullname: Kaneko, Takehito organization: Graduate School of Science and Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan – sequence: 5 fullname: Mashimo, Tomoji organization: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyou-ku, Kyoto 606-8501, Japan – sequence: 6 fullname: Yamada, Takaya organization: Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan – sequence: 7 fullname: Nabika, Toru organization: Department of Functional Pathology, Shimane University Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan |
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Cites_doi | 10.1536/ihj.14.182 10.1038/s41598-020-72338-3 10.1038/nmeth.2857 10.1016/j.atherosclerosis.2004.12.020 10.1161/CIRCRESAHA.118.314402 10.1016/j.cell.2022.04.004 10.1056/NEJMra043430 10.1371/journal.pone.0095091 10.1038/s41440-019-0207-9 10.1161/01.STR.7.2.120 10.1038/onc.2012.93 10.1161/01.HYP.25.2.155 10.1007/s11883-022-00993-0 10.1371/journal.pone.0264934 10.1126/science.1411543 10.1016/j.clinbiochem.2008.10.007 10.1161/JAHA.112.003358 10.1038/nm.2538 10.1046/j.1320-5463.2003.01465.x 10.1194/jlr.R400007-JLR200 10.1161/CIRCRESAHA.111.245530 10.1016/0092-8674(92)90362-G 10.1155/2013/103731 10.1073/pnas.1401712111 10.7555/JBR.31.20160020 10.1038/nbt.2661 10.1038/s41598-019-54541-z 10.1038/nature03587 10.1271/bbb.110059 |
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SubjectTerms | Animal models Aorta Apolipoprotein E Apolipoproteins Arteries Arteriosclerosis Atherosclerosis Blood pressure Cholesterol CRISPR Depletion Deposition Gene deletion genome editing High cholesterol diet High fat diet Hypertension Mutation Oxidative stress Peroxiredoxin peroxiredoxin 2 Salt loading spontaneously hypertensive rat Triglycerides Western blotting |
Title | Apolipoprotein E-depletion accelerates arterial fat deposition in the spontaneously hypertensive rat |
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