Inhibition of MicroRNA-494 Reduces Carotid Artery Atherosclerotic Lesion Development and Increases Plaque Stability
Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery. We made a selection of 164 genes involved in a...
Saved in:
| Published in: | Annals of surgery Vol. 262; no. 5; pp. 841 - 7; discussion 847-8 |
|---|---|
| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
01.11.2015
|
| Subjects: | |
| ISSN: | 1528-1140 |
| Online Access: | Get more information |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery.
We made a selection of 164 genes involved in atherosclerosis. Using www.targetscan.org, we determined which microRNAs potentially regulate expression of these genes. We identified multiple microRNAs from the 14q32 microRNA cluster, which is highly involved in vascular remodeling. In human plaques, collected during carotid endarterectomy surgery, we found that 14q32 microRNA (miR-494) was abundantly expressed in unstable lesions.
We induced atherosclerotic plaque formation in hypercholesterolemic ApoE mice by placing semiconstrictive collars around both carotid arteries. We injected "Gene Silencing Oligonucleotides" against miR-494 (GSO-494) or negative control (GSO-control). Using fluorescently labeled GSOs, we confirmed uptake of GSOs in affected areas of the carotids, but not elsewhere in the vasculature.
After injection of GSO-494, we observed significant downregulation of miR-494 expression in the carotid arteries, although miR-494 target genes were upregulated. Further analyses revealed a 65% decrease in plaque size after GSO-494 treatment. Plaque stability was increased in GSO-494-treated mice, determined by an 80% decrease in necrotic core size and a 50% increase in plaque collagen content. Inhibition of miR-494 also resulted in decreased cholesterol levels and decreased very low-density lipoprotein (VLDL) fractions.
Treatment with GSO-494 results in smaller atherosclerotic lesions with increased plaque stability. Inhibition of miR-494 may decrease the risk of surgical complications or even avert endarterectomy surgery in some cases. |
|---|---|
| AbstractList | Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery.
We made a selection of 164 genes involved in atherosclerosis. Using www.targetscan.org, we determined which microRNAs potentially regulate expression of these genes. We identified multiple microRNAs from the 14q32 microRNA cluster, which is highly involved in vascular remodeling. In human plaques, collected during carotid endarterectomy surgery, we found that 14q32 microRNA (miR-494) was abundantly expressed in unstable lesions.
We induced atherosclerotic plaque formation in hypercholesterolemic ApoE mice by placing semiconstrictive collars around both carotid arteries. We injected "Gene Silencing Oligonucleotides" against miR-494 (GSO-494) or negative control (GSO-control). Using fluorescently labeled GSOs, we confirmed uptake of GSOs in affected areas of the carotids, but not elsewhere in the vasculature.
After injection of GSO-494, we observed significant downregulation of miR-494 expression in the carotid arteries, although miR-494 target genes were upregulated. Further analyses revealed a 65% decrease in plaque size after GSO-494 treatment. Plaque stability was increased in GSO-494-treated mice, determined by an 80% decrease in necrotic core size and a 50% increase in plaque collagen content. Inhibition of miR-494 also resulted in decreased cholesterol levels and decreased very low-density lipoprotein (VLDL) fractions.
Treatment with GSO-494 results in smaller atherosclerotic lesions with increased plaque stability. Inhibition of miR-494 may decrease the risk of surgical complications or even avert endarterectomy surgery in some cases. OBJECTIVESUnstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery.BACKGROUNDWe made a selection of 164 genes involved in atherosclerosis. Using www.targetscan.org, we determined which microRNAs potentially regulate expression of these genes. We identified multiple microRNAs from the 14q32 microRNA cluster, which is highly involved in vascular remodeling. In human plaques, collected during carotid endarterectomy surgery, we found that 14q32 microRNA (miR-494) was abundantly expressed in unstable lesions.METHODSWe induced atherosclerotic plaque formation in hypercholesterolemic ApoE mice by placing semiconstrictive collars around both carotid arteries. We injected "Gene Silencing Oligonucleotides" against miR-494 (GSO-494) or negative control (GSO-control). Using fluorescently labeled GSOs, we confirmed uptake of GSOs in affected areas of the carotids, but not elsewhere in the vasculature.RESULTSAfter injection of GSO-494, we observed significant downregulation of miR-494 expression in the carotid arteries, although miR-494 target genes were upregulated. Further analyses revealed a 65% decrease in plaque size after GSO-494 treatment. Plaque stability was increased in GSO-494-treated mice, determined by an 80% decrease in necrotic core size and a 50% increase in plaque collagen content. Inhibition of miR-494 also resulted in decreased cholesterol levels and decreased very low-density lipoprotein (VLDL) fractions.CONCLUSIONSTreatment with GSO-494 results in smaller atherosclerotic lesions with increased plaque stability. Inhibition of miR-494 may decrease the risk of surgical complications or even avert endarterectomy surgery in some cases. |
| Author | Razawy, Wida Boonstra, Martin C Kuiper, Johan Quax, Paul H A Nossent, A Yaël Goossens, Eveline A C de Vries, Margreet R Kandimalla, Ekambar R Lagraauw, H Maxime Welten, Sabine M J Wezel, Anouk Bot, Ilze Hamming, Jaap F |
| Author_xml | – sequence: 1 givenname: Anouk surname: Wezel fullname: Wezel, Anouk organization: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands †Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands ‡Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands §Idera Pharmaceuticals, Cambridge, MA – sequence: 2 givenname: Sabine M J surname: Welten fullname: Welten, Sabine M J – sequence: 3 givenname: Wida surname: Razawy fullname: Razawy, Wida – sequence: 4 givenname: H Maxime surname: Lagraauw fullname: Lagraauw, H Maxime – sequence: 5 givenname: Margreet R surname: de Vries fullname: de Vries, Margreet R – sequence: 6 givenname: Eveline A C surname: Goossens fullname: Goossens, Eveline A C – sequence: 7 givenname: Martin C surname: Boonstra fullname: Boonstra, Martin C – sequence: 8 givenname: Jaap F surname: Hamming fullname: Hamming, Jaap F – sequence: 9 givenname: Ekambar R surname: Kandimalla fullname: Kandimalla, Ekambar R – sequence: 10 givenname: Johan surname: Kuiper fullname: Kuiper, Johan – sequence: 11 givenname: Paul H A surname: Quax fullname: Quax, Paul H A – sequence: 12 givenname: A Yaël surname: Nossent fullname: Nossent, A Yaël – sequence: 13 givenname: Ilze surname: Bot fullname: Bot, Ilze |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26583674$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNUN1LwzAcDKK4D_0PRPLoS2fSpEn7WObXYH6w6XNJk19ZpG1mkgr7791wgvdycNwdx03Qae96QOiKkhklhbxdL8sZ-QfKhThBY5qleUIpJyM0CeHzoOdEnqNRKrKcCcnHKCz6ja1ttK7HrsHPVnu3eikTXnC8AjNoCHiuvIvW4NJH8Dtcxg14F3QLB1njJYRD-g6-oXXbDvqIVW_wotceVNjn31r1NQBeR1Xb1sbdBTprVBvg8shT9PFw_z5_Spavj4t5uUw0IzImRoAkjHPG6jpjhAldUC3zlNeilkQBUQ3VuqiN0gIMa3KemYwKxdI854o16RTd_PZuvdsPCLHqbNDQtqoHN4SKSpYxlpIi21uvj9ah7sBUW2875XfV31HpDxRxa8g |
| CitedBy_id | crossref_primary_10_1186_s12872_019_1120_5 crossref_primary_10_1016_j_lfs_2019_116547 crossref_primary_10_1016_j_omtn_2020_07_020 crossref_primary_10_1016_j_omtn_2021_10_027 crossref_primary_10_1038_s41419_018_0690_y crossref_primary_10_1111_bph_17374 crossref_primary_10_3390_ijms24043861 crossref_primary_10_1016_j_pharmthera_2018_11_003 crossref_primary_10_1016_j_atherosclerosis_2017_04_011 crossref_primary_10_1007_s11883_018_0737_7 crossref_primary_10_1093_cvr_cvw039 crossref_primary_10_3390_ijms251810026 crossref_primary_10_3390_ijms23031057 crossref_primary_10_3390_ijms21103508 crossref_primary_10_3390_ijms20235975 crossref_primary_10_1371_journal_pone_0184348 crossref_primary_10_1007_s11357_019_00095_x crossref_primary_10_1016_j_atherosclerosis_2018_06_015 crossref_primary_10_1016_j_omtn_2019_09_021 crossref_primary_10_3390_ijms23063346 crossref_primary_10_1155_2019_5028181 crossref_primary_10_1093_hmg_ddab304 crossref_primary_10_1186_s12933_020_01107_3 crossref_primary_10_1134_S0006297917110165 crossref_primary_10_1016_j_bbalip_2015_12_013 crossref_primary_10_3389_fcvm_2019_00113 crossref_primary_10_3390_ijms21218236 crossref_primary_10_3390_ijms22115718 crossref_primary_10_1007_s10029_024_03202_w crossref_primary_10_3390_ijms222312678 crossref_primary_10_1042_BSR20204250 crossref_primary_10_1071_CH16020 crossref_primary_10_1093_cvr_cvy309 crossref_primary_10_1016_j_isci_2024_110988 |
| ContentType | Journal Article |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1097/SLA.0000000000001466 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| EISSN | 1528-1140 |
| EndPage | 7; discussion 847-8 |
| ExternalDocumentID | 26583674 |
| Genre | Research Support, Non-U.S. Gov't Journal Article |
| GroupedDBID | --- .-D .3C .55 .GJ .XZ .Z2 01R 0R~ 1J1 23M 2WC 354 3O- 40H 4Q1 4Q2 4Q3 53G 5GY 5VS 6J9 71W 77Y 7O~ AAAAV AAAXR AAEJM AAFWJ AAGIX AAHPQ AAIQE AAJCS AAMOA AAMTA AAQKA AARTV AASCR AASOK AASXQ AAUEB AAXQO ABASU ABBUW ABDIG ABJNI ABOCM ABPMR ABPPZ ABPXF ABVCZ ABXVJ ABXYN ABZAD ABZZY ACCJW ACDDN ACDOF ACEWG ACGFO ACGFS ACILI ACLDA ACOAL ACWDW ACWRI ACXJB ACXNZ ACZKN ADBBV ADFPA ADGGA ADHPY ADNKB AE3 AE6 AEBDS AEETU AENEX AFBFQ AFCHL AFDTB AFEXH AFMBP AFNMH AFSOK AFUWQ AGINI AHJKT AHOMT AHQNM AHQVU AHRYX AHVBC AI. AIJEX AINUH AJCLO AJIOK AJJEV AJNWD AJNYG AJZMW AKCTQ AKULP ALKUP ALMA_UNASSIGNED_HOLDINGS ALMTX AMJPA AMKUR AMNEI AOHHW AOQMC ASPBG AVWKF AZFZN BAWUL BOYCO BQLVK BS7 BYPQX C45 CGR CS3 CUY CVF DIK DIWNM DUNZO E.X E3Z EBS ECM EEVPB EIF EJD ERAAH EX3 F2K F2L F2M F2N F5P FCALG FEDTE FL- FW0 GNXGY GQDEL H0~ HLJTE HVGLF HZ~ IH2 IKREB IKYAY IN~ IPNFZ J5H JF7 JF9 JG8 JK3 JK8 K-A K-F K8S KD2 KMI L-C L7B M18 N4W N9A NPM N~7 N~B N~M O9- OAG OAH OBH OCB OCUKA ODA ODMTH OGEVE OHH OHYEH OK1 OL1 OLB OLG OLH OLU OLV OLY OLZ OPUJH ORVUJ OUVQU OVD OVDNE OVIDH OVLEI OVOZU OWBYB OWU OWV OWW OWX OWY OWZ OXXIT P-K P2P R58 RIG RLZ RPM RXW S4R S4S T8P TAF TEORI TR2 TSPGW UQX V2I VH1 VVN W3M WH7 WOQ WOW X3V X3W X7M XXN XYM YFH YOC ZFV ZGI ZXP ZY1 ZZMQN ~H1 7X8 ACBKD ADKSD ADSXY |
| ID | FETCH-LOGICAL-c307t-d6e7034433bb53036c91c7824b6b70ae0af1cc9bdac6ed3f845d516a32884a3f2 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 38 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000368011900020&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| IngestDate | Sun Nov 09 09:45:32 EST 2025 Mon Jul 21 05:21:56 EDT 2025 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 5 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c307t-d6e7034433bb53036c91c7824b6b70ae0af1cc9bdac6ed3f845d516a32884a3f2 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| PMID | 26583674 |
| PQID | 1735332095 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_1735332095 pubmed_primary_26583674 |
| PublicationCentury | 2000 |
| PublicationDate | 2015-Nov 20151101 |
| PublicationDateYYYYMMDD | 2015-11-01 |
| PublicationDate_xml | – month: 11 year: 2015 text: 2015-Nov |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Annals of surgery |
| PublicationTitleAlternate | Ann Surg |
| PublicationYear | 2015 |
| SSID | ssj0014807 |
| Score | 2.3582342 |
| Snippet | Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that... OBJECTIVESUnstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 841 |
| SubjectTerms | Animals Atherosclerosis - genetics Atherosclerosis - metabolism Blotting, Western Carotid Arteries Disease Models, Animal DNA - genetics Gene Expression Regulation Humans Male Mice MicroRNAs - biosynthesis MicroRNAs - genetics Plaque, Atherosclerotic - genetics Plaque, Atherosclerotic - metabolism Reverse Transcriptase Polymerase Chain Reaction |
| Title | Inhibition of MicroRNA-494 Reduces Carotid Artery Atherosclerotic Lesion Development and Increases Plaque Stability |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/26583674 https://www.proquest.com/docview/1735332095 |
| Volume | 262 |
| WOSCitedRecordID | wos000368011900020&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV3dS8MwEA_qfPDFD_z-IoKvwbZJm_VJhjgUtjH8Ym8juaQ4kHauU_C_967tmC-CYB8KLVxJ0svdL7lf7hi7dFHmU_RzIsy0Ekp6JUygrXDEXMuC2NUkmpeeHgzao1E6bDbcyoZWubCJlaF2BdAe-VWoJSKTCBHB9fRdUNUoiq42JTRWWUsilCGt1qNlFIGOSy-Oy6X66rHXqdMVNhcaieR3YFk5mO7Wf5u2zTYbaMk7tS7ssBWf77LyPn-d2IqXxYuM94l_9zDoCJUq_kBpW33JifQxnziS9LMv3iFMWJT4DXoNvOdpR43_oBdxkzuOloUI7Sg_fDPYXI64tWLafu2x5-7t082daAotCMApPhcu8ZpS_0lpbUw-DdIQEDoom1gdGB-YLARIrTOQeCeztopdHCZGRu22MjKL9tlaXuT-kHEACWCVUhb7oQLA5RwEAPhgVIRrkyN2sRjDMSoyRSdM7ouPcrwcxSN2UP-I8bTOuDGOECfJRKvjP0ifsA0ENXF9XvCUtTKcxv6MrcPnfFLOzisNwftg2P8GA-bHJA |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Inhibition+of+MicroRNA-494+Reduces+Carotid+Artery+Atherosclerotic+Lesion+Development+and+Increases+Plaque+Stability&rft.jtitle=Annals+of+surgery&rft.au=Wezel%2C+Anouk&rft.au=Welten%2C+Sabine+M+J&rft.au=Razawy%2C+Wida&rft.au=Lagraauw%2C+H+Maxime&rft.date=2015-11-01&rft.eissn=1528-1140&rft.volume=262&rft.issue=5&rft.spage=841&rft.epage=7%3B+discussion+847-8&rft_id=info:doi/10.1097%2FSLA.0000000000001466&rft.externalDBID=NO_FULL_TEXT |