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Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2
Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site-specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and dis...
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| Published in: | Journal of the American Heart Association 2015-02, Vol.4 (2) |
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| container_title | Journal of the American Heart Association |
| container_volume | 4 |
| creator | Fenning, Robert S Burgert, Mark E Hamamdzic, Damir Peyster, Eliot G Mohler, Emile R Kangovi, Shreya Jucker, Beat M Lenhard, Stephen C Macphee, Colin H Wilensky, Robert L |
| description | Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site-specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and distal abdominal aortas (AAs).
Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site-specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp-PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site-specific differences in plaque severity. In the AAs, normalized plaque area was 4.4-fold higher (P |
| doi_str_mv | 10.1161/JAHA.114.001477 |
| format | article |
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Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site-specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp-PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site-specific differences in plaque severity. In the AAs, normalized plaque area was 4.4-fold higher (P<0.001) and there were more fibroatheromas (9 of the 17 animals had a fibroatheroma in the AA and not the COR, P=0.004), while normalized macrophage staining area was 1.5-fold higher (P=0.011) compared with CORs. DM/HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the CORs. Darapladib-induced attenuation of normalized plaque area was site-specific, as CORs responded 2.9-fold more than AAs (P=0.045).
While plaque severity was worse in the AAs, inflammatory genes and inflammatory pathways that use Lp-PLA2 were more important in the CORs. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti-inflammatory therapeutics.</description><identifier>EISSN: 2047-9980</identifier><identifier>DOI: 10.1161/JAHA.114.001477</identifier><identifier>PMID: 25672369</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors ; Animals ; Aorta, Abdominal - immunology ; Aorta, Abdominal - pathology ; Atherosclerosis - metabolism ; Benzaldehydes - pharmacology ; Coronary Vessels - immunology ; Coronary Vessels - pathology ; Diabetes Mellitus - immunology ; Diabetes Mellitus - pathology ; Disease Models, Animal ; Gene Expression - drug effects ; Hypercholesterolemia - immunology ; Hypercholesterolemia - pathology ; Inflammation - metabolism ; Macrophages - immunology ; Male ; Original Research ; Oximes - pharmacology ; Phospholipase A2 Inhibitors - pharmacology ; Plaque, Atherosclerotic - metabolism ; Plaque, Atherosclerotic - pathology ; Swine</subject><ispartof>Journal of the American Heart Association, 2015-02, Vol.4 (2)</ispartof><rights>2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.</rights><rights>2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345873/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345873/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25672369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fenning, Robert S</creatorcontrib><creatorcontrib>Burgert, Mark E</creatorcontrib><creatorcontrib>Hamamdzic, Damir</creatorcontrib><creatorcontrib>Peyster, Eliot G</creatorcontrib><creatorcontrib>Mohler, Emile R</creatorcontrib><creatorcontrib>Kangovi, Shreya</creatorcontrib><creatorcontrib>Jucker, Beat M</creatorcontrib><creatorcontrib>Lenhard, Stephen C</creatorcontrib><creatorcontrib>Macphee, Colin H</creatorcontrib><creatorcontrib>Wilensky, Robert L</creatorcontrib><title>Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2</title><title>Journal of the American Heart Association</title><addtitle>J Am Heart Assoc</addtitle><description>Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site-specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and distal abdominal aortas (AAs).
Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site-specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp-PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site-specific differences in plaque severity. In the AAs, normalized plaque area was 4.4-fold higher (P<0.001) and there were more fibroatheromas (9 of the 17 animals had a fibroatheroma in the AA and not the COR, P=0.004), while normalized macrophage staining area was 1.5-fold higher (P=0.011) compared with CORs. DM/HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the CORs. Darapladib-induced attenuation of normalized plaque area was site-specific, as CORs responded 2.9-fold more than AAs (P=0.045).
While plaque severity was worse in the AAs, inflammatory genes and inflammatory pathways that use Lp-PLA2 were more important in the CORs. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti-inflammatory therapeutics.</description><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors</subject><subject>Animals</subject><subject>Aorta, Abdominal - immunology</subject><subject>Aorta, Abdominal - pathology</subject><subject>Atherosclerosis - metabolism</subject><subject>Benzaldehydes - pharmacology</subject><subject>Coronary Vessels - immunology</subject><subject>Coronary Vessels - pathology</subject><subject>Diabetes Mellitus - immunology</subject><subject>Diabetes Mellitus - pathology</subject><subject>Disease Models, Animal</subject><subject>Gene Expression - drug effects</subject><subject>Hypercholesterolemia - immunology</subject><subject>Hypercholesterolemia - pathology</subject><subject>Inflammation - metabolism</subject><subject>Macrophages - immunology</subject><subject>Male</subject><subject>Original Research</subject><subject>Oximes - pharmacology</subject><subject>Phospholipase A2 Inhibitors - pharmacology</subject><subject>Plaque, Atherosclerotic - metabolism</subject><subject>Plaque, Atherosclerotic - pathology</subject><subject>Swine</subject><issn>2047-9980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNpVkUFP3jAMhqNJCBBw5jblyKUsaZImvSBVaPANIe2ynSs3dWmmtOmSfKD9kv3dBQYTs5TYju3nlWJCzjm75Lzhn-66XVcieckYl1p_IMc1k7pqW8OOyFlKP1ixptZCtYfkqFaNrkXTHpPfXZ4xhmR9ubOzdPPwc4_UrZOHZYHswkofITpMdMD8hPicJrv3EGlyuTzDOlIbYkQPz-mTyzONmLawJqQ5FNTsBvcCChP1bgtbkUK3VpBSsK5MjXSbQyqnVKFMdfUpOZjAJzx79Sfk-83nb9e76v7r7Zfr7r7auOG5moS1FifJlNKyNgzbAa0UrTQgjJjAqnFohW5GVBb5yMYauQHUYwmMmRpxQq7-crf9sOBocc0RfL9Ft0D81Qdw_f-V1c39Q3jspZDKaFEAF6-AGMrHpdwvLln0HlYM-9TzRqlaaa15af34XuufyNs2xB_zDJI4</recordid><startdate>20150211</startdate><enddate>20150211</enddate><creator>Fenning, Robert S</creator><creator>Burgert, Mark E</creator><creator>Hamamdzic, Damir</creator><creator>Peyster, Eliot G</creator><creator>Mohler, Emile R</creator><creator>Kangovi, Shreya</creator><creator>Jucker, Beat M</creator><creator>Lenhard, Stephen C</creator><creator>Macphee, Colin H</creator><creator>Wilensky, Robert L</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150211</creationdate><title>Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2</title><author>Fenning, Robert S ; Burgert, Mark E ; Hamamdzic, Damir ; Peyster, Eliot G ; Mohler, Emile R ; Kangovi, Shreya ; Jucker, Beat M ; Lenhard, Stephen C ; Macphee, Colin H ; Wilensky, Robert L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p181t-f3cccef405574280e9bec43948a383fac5db9376de5ce1d0d2e18ae7dd2e88f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors</topic><topic>Animals</topic><topic>Aorta, Abdominal - immunology</topic><topic>Aorta, Abdominal - pathology</topic><topic>Atherosclerosis - metabolism</topic><topic>Benzaldehydes - pharmacology</topic><topic>Coronary Vessels - immunology</topic><topic>Coronary Vessels - pathology</topic><topic>Diabetes Mellitus - immunology</topic><topic>Diabetes Mellitus - pathology</topic><topic>Disease Models, Animal</topic><topic>Gene Expression - drug effects</topic><topic>Hypercholesterolemia - immunology</topic><topic>Hypercholesterolemia - pathology</topic><topic>Inflammation - metabolism</topic><topic>Macrophages - immunology</topic><topic>Male</topic><topic>Original Research</topic><topic>Oximes - pharmacology</topic><topic>Phospholipase A2 Inhibitors - pharmacology</topic><topic>Plaque, Atherosclerotic - metabolism</topic><topic>Plaque, Atherosclerotic - pathology</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fenning, Robert S</creatorcontrib><creatorcontrib>Burgert, Mark E</creatorcontrib><creatorcontrib>Hamamdzic, Damir</creatorcontrib><creatorcontrib>Peyster, Eliot G</creatorcontrib><creatorcontrib>Mohler, Emile R</creatorcontrib><creatorcontrib>Kangovi, Shreya</creatorcontrib><creatorcontrib>Jucker, Beat M</creatorcontrib><creatorcontrib>Lenhard, Stephen C</creatorcontrib><creatorcontrib>Macphee, Colin H</creatorcontrib><creatorcontrib>Wilensky, Robert L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Heart Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fenning, Robert S</au><au>Burgert, Mark E</au><au>Hamamdzic, Damir</au><au>Peyster, Eliot G</au><au>Mohler, Emile R</au><au>Kangovi, Shreya</au><au>Jucker, Beat M</au><au>Lenhard, Stephen C</au><au>Macphee, Colin H</au><au>Wilensky, Robert L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2</atitle><jtitle>Journal of the American Heart Association</jtitle><addtitle>J Am Heart Assoc</addtitle><date>2015-02-11</date><risdate>2015</risdate><volume>4</volume><issue>2</issue><eissn>2047-9980</eissn><abstract>Despite systemic exposure to risk factors, the circulatory system develops varying patterns of atherosclerosis for unclear reasons. In a porcine model, we investigated the relationship between site-specific lesion development and inflammatory pathways involved in the coronary arteries (CORs) and distal abdominal aortas (AAs).
Diabetes mellitus (DM) and hypercholesterolemia (HC) were induced in 37 pigs with 3 healthy controls. Site-specific plaque development was studied by comparing plaque severity, macrophage infiltration, and inflammatory gene expression between CORs and AAs of 17 DM/HC pigs. To assess the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in plaque development, 20 DM/HC pigs were treated with the Lp-PLA2 inhibitor darapladib and compared with the 17 DM/HC untreated pigs. DM/HC caused site-specific differences in plaque severity. In the AAs, normalized plaque area was 4.4-fold higher (P<0.001) and there were more fibroatheromas (9 of the 17 animals had a fibroatheroma in the AA and not the COR, P=0.004), while normalized macrophage staining area was 1.5-fold higher (P=0.011) compared with CORs. DM/HC caused differential expression of 8 of 87 atherosclerotic genes studied, including 3 important in inflammation with higher expression in the CORs. Darapladib-induced attenuation of normalized plaque area was site-specific, as CORs responded 2.9-fold more than AAs (P=0.045).
While plaque severity was worse in the AAs, inflammatory genes and inflammatory pathways that use Lp-PLA2 were more important in the CORs. Our results suggest fundamental differences in inflammation between vascular sites, an important finding for the development of novel anti-inflammatory therapeutics.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>25672369</pmid><doi>10.1161/JAHA.114.001477</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of the American Heart Association, 2015-02, Vol.4 (2) |
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| source | Open Access: PubMed Central; Open Access: Wiley-Blackwell Open Access Journals |
| subjects | 1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors Animals Aorta, Abdominal - immunology Aorta, Abdominal - pathology Atherosclerosis - metabolism Benzaldehydes - pharmacology Coronary Vessels - immunology Coronary Vessels - pathology Diabetes Mellitus - immunology Diabetes Mellitus - pathology Disease Models, Animal Gene Expression - drug effects Hypercholesterolemia - immunology Hypercholesterolemia - pathology Inflammation - metabolism Macrophages - immunology Male Original Research Oximes - pharmacology Phospholipase A2 Inhibitors - pharmacology Plaque, Atherosclerotic - metabolism Plaque, Atherosclerotic - pathology Swine |
| title | Atherosclerotic plaque inflammation varies between vascular sites and correlates with response to inhibition of lipoprotein-associated phospholipase A2 |
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