{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:04:50Z","timestamp":1792613090063,"version":"4.5.0"},"reference-count":87,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA. To test the hypothesis that elevated plasma TG levels accelerate AAA development, we used\n                      <jats:italic toggle=\"yes\">Lpl<\/jats:italic>\n                      -deficient,\n                      <jats:italic toggle=\"yes\">Apoa5<\/jats:italic>\n                      -deficient, and human\n                      <jats:italic toggle=\"yes\">APOC3<\/jats:italic>\n                      transgenic mice, which display varying degrees of hypertriglyceridemia. Mechanistic studies were performed using RNA sequencing and Western blot analysis of palmitate-treated vascular smooth muscle cells and validated in vivo by local overexpression of key mediator in the suprarenal abdominal aorta. Antisense oligonucleotides targeting\n                      <jats:italic toggle=\"yes\">Angptl3<\/jats:italic>\n                      were administered to reduce TG levels and assess therapeutic potential in human\n                      <jats:italic toggle=\"yes\">APOC3<\/jats:italic>\n                      transgenic and\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      -deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified causal relationships between elevated TG-rich lipoproteins, TG metabolism\u2013related proteins\/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most\n                      <jats:italic toggle=\"yes\">Lpl<\/jats:italic>\n                      -deficient mice with severely elevated TG concentrations died of aortic rupture. Similarly,\n                      <jats:italic toggle=\"yes\">Apoa5<\/jats:italic>\n                      -deficient mice with moderately elevated TG levels developed accelerated AAA, and human\n                      <jats:italic toggle=\"yes\">APOC3<\/jats:italic>\n                      transgenic mice with dramatically elevated TG levels exhibited aortic dissection and rupture. Mechanistically, elevated TG and palmitate inhibited lysyl oxidase (LOX) maturation and reduced LOX activity. Locally overexpressing lysyl oxidase eliminated the proaneurysmal effect of hypertriglyceridemia in human\n                      <jats:italic toggle=\"yes\">APOC3<\/jats:italic>\n                      transgenic mice. Moreover, an\n                      <jats:italic toggle=\"yes\">Angptl3<\/jats:italic>\n                      -targeting antisense oligonucleotide profoundly attenuated AAA progression in both human\n                      <jats:italic toggle=\"yes\">APOC3<\/jats:italic>\n                      transgenic and\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      -deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings identify hypertriglyceridemia as a key contributor to AAA pathogenesis and suggest that targeting TG-rich lipoproteins may be a promising therapeutic strategy for AAA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074737","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T09:00:09Z","timestamp":1754384409000},"page":"862-881","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights From Genetic and Experimental Models"],"prefix":"10.1161","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6187-6055","authenticated-orcid":true,"given":"Yaozhong","family":"Liu","sequence":"first","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilun","family":"Wang","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."},{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville (H.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minzhi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor (M.Y., A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8535-530X","authenticated-orcid":true,"given":"Lei","family":"Cai","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington (L.C., H.S.L., A.D., R.E.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7022-9391","authenticated-orcid":true,"given":"Ying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0931-6237","authenticated-orcid":true,"given":"Yongjie","family":"Deng","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1428-5145","authenticated-orcid":true,"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5740-8010","authenticated-orcid":true,"given":"Haocheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Southern University of Science and Technology, Guangdong, China (H. Lu)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1020-6232","authenticated-orcid":true,"given":"Xiaokang","family":"Wu","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."},{"name":"College of Pharmacy Health, University of Houston, Houston, TX (G.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6528-3975","authenticated-orcid":true,"given":"Chao","family":"Xue","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."},{"name":"Department of Internal Medicine, Rochester General Hospital, Rochester, NY (C.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-5541","authenticated-orcid":true,"given":"Ida","family":"Surakka","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-8080","authenticated-orcid":true,"given":"Anna","family":"Schwendeman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor (M.Y., A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0577-2558","authenticated-orcid":true,"given":"Hong S.","family":"Lu","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington (L.C., H.S.L., A.D., R.E.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2093-3775","authenticated-orcid":true,"given":"Alan","family":"Daugherty","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington (L.C., H.S.L., A.D., R.E.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5621-8426","authenticated-orcid":true,"given":"Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. 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Eugene","family":"Chen","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."},{"name":"Center for Advanced Models for Translational Sciences and Therapeutics (Y.E.C.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3334-9159","authenticated-orcid":true,"given":"Yanhong","family":"Guo","sequence":"additional","affiliation":[{"name":"Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2010.180"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa013527"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2016.02.055"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.9235"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad386"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01510-y"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2017.4293"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0222-9"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.1800720215"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/27.6.949"},{"key":"e_1_3_3_12_2","volume-title":"Endotext","author":"Subramanian S","year":"2000","unstructured":"Subramanian S. 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