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Article: Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation In Apolipoprotein E-null Mice

TitleAldose Reductase Protects Against Early Atherosclerotic Lesion Formation In Apolipoprotein E-null Mice
Authors
Issue Date2009
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 2009, v. 105 n. 8, p. 793-802 How to Cite?
AbstractRATIONALE: Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion; however, their contribution to atherosclerotic lesion formation remains unclear. OBJECTIVE: To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, exacerbates atherosclerotic lesion formation. METHODS AND RESULTS: In atherosclerotic lesions of apolipoprotein (apo)E-null mice, AR protein was located in macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation but did not affect the formation of advanced lesions. Early lesions of AR(-/-)/apoE(-/-) mice maintained on high-fat diet were significantly larger when compared with age-matched AR(+/+)/apoE(-/-) mice. The increase in lesion area attributable to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR(-/-)/apoE(-/-) mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR(-/-)/apoE(-/-) mice displayed a greater accumulation of the AR substrate 4-hydroxy trans-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR(+/+)/apoE(-/-) mice. CONCLUSIONS: These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.
Persistent Identifierhttp://hdl.handle.net/10722/81233
ISSN
2015 Impact Factor: 11.551
2015 SCImago Journal Rankings: 5.755
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorSrivastava, Sen_HK
dc.contributor.authorVladykovskaya, Een_HK
dc.contributor.authorBarski, OAen_HK
dc.contributor.authorSpite, Men_HK
dc.contributor.authorKaiserova, Ken_HK
dc.contributor.authorPetrash, JMen_HK
dc.contributor.authorChung, SSen_HK
dc.contributor.authorHunt, Gen_HK
dc.contributor.authorDawn, Ben_HK
dc.contributor.authorBhatnagar, Aen_HK
dc.date.accessioned2010-09-06T08:15:20Z-
dc.date.available2010-09-06T08:15:20Z-
dc.date.issued2009en_HK
dc.identifier.citationCirculation Research, 2009, v. 105 n. 8, p. 793-802en_HK
dc.identifier.issn0009-7330en_HK
dc.identifier.urihttp://hdl.handle.net/10722/81233-
dc.description.abstractRATIONALE: Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion; however, their contribution to atherosclerotic lesion formation remains unclear. OBJECTIVE: To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, exacerbates atherosclerotic lesion formation. METHODS AND RESULTS: In atherosclerotic lesions of apolipoprotein (apo)E-null mice, AR protein was located in macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation but did not affect the formation of advanced lesions. Early lesions of AR(-/-)/apoE(-/-) mice maintained on high-fat diet were significantly larger when compared with age-matched AR(+/+)/apoE(-/-) mice. The increase in lesion area attributable to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR(-/-)/apoE(-/-) mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR(-/-)/apoE(-/-) mice displayed a greater accumulation of the AR substrate 4-hydroxy trans-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR(+/+)/apoE(-/-) mice. CONCLUSIONS: These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.-
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.rightsThis is a non-final version of an article published in final form in (provide complete journal citation)en_HK
dc.subject.meshAldehyde Reductase - genetics - metabolism-
dc.subject.meshAldehydes - metabolism-
dc.subject.meshApolipoproteins E-
dc.subject.meshAtherosclerosis - enzymology - genetics - prevention & control-
dc.subject.meshPhospholipids - genetics - metabolism-
dc.titleAldose Reductase Protects Against Early Atherosclerotic Lesion Formation In Apolipoprotein E-null Miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0009-7330&volume=105&spage=793&epage=802&date=2009&atitle=Aldose+Reductase+Protects+Against+Early+Atherosclerotic+Lesion+Formation+In+Apolipoprotein+E-null+Micen_HK
dc.identifier.emailChung, SS: smchung@hkucc.hku.hken_HK
dc.identifier.authorityChung, SSM=rp00376en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1161/CIRCRESAHA.109.200568-
dc.identifier.pmid19729598-
dc.identifier.pmcidPMC3548455-
dc.identifier.hkuros167840en_HK
dc.identifier.volume105-
dc.identifier.issue8-
dc.identifier.spage793-
dc.identifier.epage802-
dc.publisher.placeUnited States-

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