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Article: Human paraoxonase gene cluster transgenic overexpression represses atherogenesis and promotes atherosclerotic plaque stability in ApoE-Null Mice

TitleHuman paraoxonase gene cluster transgenic overexpression represses atherogenesis and promotes atherosclerotic plaque stability in ApoE-Null Mice
Authors
KeywordsAtherosclerosis
Macrophages
Paraoxonase cluster
Plaques stability
Issue Date2009
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 2009, v. 104 n. 10, p. 1160-1168 How to Cite?
AbstractThe paraoxonase (PON) gene cluster consists of the PON1, PON2, and PON3 genes, each of which can individually inhibit atherogenesis. To analyze the functions of the PON gene cluster (PC) in atherogenesis and plaque stability, human PC transgenic (Tg) mice were generated using bacterial artificial chromosome. The high-density lipoprotein from Tg mice exhibited increased paraoxonase activity. When crossed to the ApoE-null background and challenged by high-fat diet, PC Tg/ApoE-null mice formed significantly fewer atherosclerotic lesions. However overexpression of the PC transgene had no additive effect on atherosclerosis compared to the overexpression of the single PON1 or PON3 transgene. Plaques from PC Tg/ApoE-null mice exhibited increased levels of collagen and smooth muscle cells, and reduced levels of macrophages and lipid, compared with those from ApoE-null mice, indicating lesions of PC Tg/ApoE-null mice had characteristics of more stable plaques than those of ApoE-null mice. PC transgene enhanced high-density lipoprotein ability to protect low-density lipoprotein against oxidation in vitro. Serum intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were also repressed by PC transgene. Proatherogenic reactions of Tg mouse peritoneal macrophages induced by oxidized low-density lipoprotein were inhibited by PC transgene, as indicated by reduced reactive oxygen species generation, inflammation, matrix metalloproteinase-9 expression, and foam cell formation. Our results demonstrate that the PC transgene not only represses atherogenesis but also promotes atherosclerotic plaque stability in vivo. PC may therefore be a useful target for atherosclerosis treatment. © 2009 American Heart Association, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/58278
ISSN
2015 Impact Factor: 11.551
2015 SCImago Journal Rankings: 5.755
ISI Accession Number ID
Funding AgencyGrant Number
National Basic Research Program of China2005CB522507
2006CB503801
National Natural Science Foundation of China30500297
30529002
30721063
National 863 project2006AA02A406
Funding Information:

This work was supported by National Basic Research Program of China grants 2005CB522507 and 2006CB503801; National Natural Science Foundation of China grants 30500297, 30529002, and 30721063; and National 863 project grant 2006AA02A406.

References

 

DC FieldValueLanguage
dc.contributor.authorShe, ZGen_HK
dc.contributor.authorZheng, Wen_HK
dc.contributor.authorWei, YSen_HK
dc.contributor.authorChen, HZen_HK
dc.contributor.authorWang, ABen_HK
dc.contributor.authorLi, HLen_HK
dc.contributor.authorLiu, Gen_HK
dc.contributor.authorZhang, Ren_HK
dc.contributor.authorLiu, JJen_HK
dc.contributor.authorStallcup, WBen_HK
dc.contributor.authorZhou, Zen_HK
dc.contributor.authorLiu, DPen_HK
dc.contributor.authorLiang, CCen_HK
dc.date.accessioned2010-05-31T03:27:18Z-
dc.date.available2010-05-31T03:27:18Z-
dc.date.issued2009en_HK
dc.identifier.citationCirculation Research, 2009, v. 104 n. 10, p. 1160-1168en_HK
dc.identifier.issn0009-7330en_HK
dc.identifier.urihttp://hdl.handle.net/10722/58278-
dc.description.abstractThe paraoxonase (PON) gene cluster consists of the PON1, PON2, and PON3 genes, each of which can individually inhibit atherogenesis. To analyze the functions of the PON gene cluster (PC) in atherogenesis and plaque stability, human PC transgenic (Tg) mice were generated using bacterial artificial chromosome. The high-density lipoprotein from Tg mice exhibited increased paraoxonase activity. When crossed to the ApoE-null background and challenged by high-fat diet, PC Tg/ApoE-null mice formed significantly fewer atherosclerotic lesions. However overexpression of the PC transgene had no additive effect on atherosclerosis compared to the overexpression of the single PON1 or PON3 transgene. Plaques from PC Tg/ApoE-null mice exhibited increased levels of collagen and smooth muscle cells, and reduced levels of macrophages and lipid, compared with those from ApoE-null mice, indicating lesions of PC Tg/ApoE-null mice had characteristics of more stable plaques than those of ApoE-null mice. PC transgene enhanced high-density lipoprotein ability to protect low-density lipoprotein against oxidation in vitro. Serum intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were also repressed by PC transgene. Proatherogenic reactions of Tg mouse peritoneal macrophages induced by oxidized low-density lipoprotein were inhibited by PC transgene, as indicated by reduced reactive oxygen species generation, inflammation, matrix metalloproteinase-9 expression, and foam cell formation. Our results demonstrate that the PC transgene not only represses atherogenesis but also promotes atherosclerotic plaque stability in vivo. PC may therefore be a useful target for atherosclerosis treatment. © 2009 American Heart Association, Inc.en_HK
dc.languageengen_HK
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.orgen_HK
dc.relation.ispartofCirculation Researchen_HK
dc.rightsCirculation Research. Copyright © Lippincott Williams & Wilkins.en_HK
dc.subjectAtherosclerosisen_HK
dc.subjectMacrophagesen_HK
dc.subjectParaoxonase clusteren_HK
dc.subjectPlaques stabilityen_HK
dc.titleHuman paraoxonase gene cluster transgenic overexpression represses atherogenesis and promotes atherosclerotic plaque stability in ApoE-Null Miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0009-7330&volume=104&spage=1160&epage=1168&date=2009&atitle=Human+paraoxonase+gene+cluster+transgenic+overexpression+represses+atherogenesis+and+promotes+atherosclerotic+plaque+stability+in+ApoE-null+mice.en_HK
dc.identifier.emailZhou, Z:zhongjun@hkucc.hku.hken_HK
dc.identifier.authorityZhou, Z=rp00503en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1161/CIRCRESAHA.108.192229en_HK
dc.identifier.scopuseid_2-s2.0-66949179058en_HK
dc.identifier.hkuros167557en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66949179058&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume104en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1160en_HK
dc.identifier.epage1168en_HK
dc.identifier.isiWOS:000266300600007-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridShe, ZG=35082612100en_HK
dc.identifier.scopusauthoridZheng, W=35381589100en_HK
dc.identifier.scopusauthoridWei, YS=14029268400en_HK
dc.identifier.scopusauthoridChen, HZ=14027920100en_HK
dc.identifier.scopusauthoridWang, AB=7404620451en_HK
dc.identifier.scopusauthoridLi, HL=16175456100en_HK
dc.identifier.scopusauthoridLiu, G=35181615300en_HK
dc.identifier.scopusauthoridZhang, R=15078578900en_HK
dc.identifier.scopusauthoridLiu, JJ=35181605100en_HK
dc.identifier.scopusauthoridStallcup, WB=7006648244en_HK
dc.identifier.scopusauthoridZhou, Z=8631856300en_HK
dc.identifier.scopusauthoridLiu, DP=8782684300en_HK
dc.identifier.scopusauthoridLiang, CC=7403280685en_HK

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