PMID- 31229835 OWN - NLM STAT- MEDLINE DCOM- 20200708 LR - 20231014 IS - 1879-1484 (Electronic) IS - 0021-9150 (Print) IS - 0021-9150 (Linking) VI - 287 DP - 2019 Aug TI - CD13 deficiency leads to increased oxidative stress and larger atherosclerotic lesions. PG - 70-80 LID - S0021-9150(19)31369-3 [pii] LID - 10.1016/j.atherosclerosis.2019.06.901 [doi] AB - BACKGROUND AND AIMS: Atherosclerosis is an inflammatory cardiovascular disorder characterized by accumulation of lipid-loaded macrophages in the intima. Prolonged accumulation leads to apoptosis of macrophages and eventually to progression of lesion development. Prevention of macrophage accumulation within the intima has been shown to reduce lesion formation. Since CD13 mediates trafficking of macrophages to sites of injury and repair, we tested the role of CD13 in atherosclerosis. METHODS: CD13(+/+)Ldlr(-/-) and CD13(-/-)Ldlr(-/-) (low density lipoprotein receptor) mice were fed basal or high fat diet (HFD) for 9, 12 and 15 weeks. Mice were euthanized and aortic roots along with innominate arteries were analyzed for atherosclerotic lesions. Cellular mechanisms were determined in vitro using CD13(+/+) and CD13(-/-) bone marrow derived macrophages (BMDMs) incubated with highly oxidized low-density lipoprotein (oxLDL). RESULTS: At the 9 and 12 week time points, no differences were observed in the average lesion size, but at the 15 week time point, CD13(-/-)Ldlr(-/-) mice had larger lesions with exaggerated necrotic areas. CD13(+/+) and CD13(-/-) macrophages endocytosed similar amounts of oxLDL, but CD13(-/-) macrophages generated higher amounts of oxidative stressors in comparison to CD13(+/+) macrophages. This increased oxidative stress was due to increased nitric oxide production in oxLDL treated CD13(-/-) macrophages. Accumulated oxidative stress subsequently led to accelerated apoptosis and enhanced necrosis of oxLDL treated CD13(-/-) macrophages. CONCLUSIONS: Contrary to our prediction, CD13 deficiency led to larger atherosclerotic lesions with increased areas of necrosis. Mechanistically, CD13 deficiency led to increased nitric oxide production and consequently, greater oxidative stress. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Devarakonda, Charan V AU - Devarakonda CV AD - Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT, 06030, USA. FAU - Pereira, Flavia E AU - Pereira FE AD - Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT, 06030, USA. FAU - Smith, Jonathan D AU - Smith JD AD - Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. FAU - Shapiro, Linda H AU - Shapiro LH AD - Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT, 06030, USA. Electronic address: lshapiro@uchc.edu. FAU - Ghosh, Mallika AU - Ghosh M AD - Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT, 06030, USA. Electronic address: mghosh@uchc.edu. LA - eng GR - P01 HL029582/HL/NHLBI NIH HHS/United States GR - P01 HL070694/HL/NHLBI NIH HHS/United States GR - R01 HL125186/HL/NHLBI NIH HHS/United States GR - R01 HL127449/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190613 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - 0 (Reactive Nitrogen Species) RN - 0 (Reactive Oxygen Species) RN - EC 3.4.11.2 (CD13 Antigens) SB - IM MH - Animals MH - Apoptosis MH - Atherosclerosis/*metabolism/pathology MH - CD13 Antigens/*deficiency/metabolism MH - Cells, Cultured MH - Disease Models, Animal MH - Immunoblotting MH - In Situ Nick-End Labeling MH - Macrophages/*metabolism/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - *Oxidative Stress MH - Reactive Nitrogen Species/metabolism MH - Reactive Oxygen Species/metabolism PMC - PMC6746312 MID - NIHMS1043290 OTO - NOTNLM OT - ANPEP OT - Atherosclerosis OT - CD13 OT - L-NMMA OT - Macrophages OT - NAC OT - Nitric oxide OT - Oxidative stress OT - Reactive nitrogen species OT - Reactive oxygen species OT - oxLDL EDAT- 2019/06/24 06:00 MHDA- 2020/07/09 06:00 PMCR- 2020/08/01 CRDT- 2019/06/24 06:00 PHST- 2018/05/31 00:00 [received] PHST- 2019/06/06 00:00 [revised] PHST- 2019/06/12 00:00 [accepted] PHST- 2019/06/24 06:00 [pubmed] PHST- 2020/07/09 06:00 [medline] PHST- 2019/06/24 06:00 [entrez] PHST- 2020/08/01 00:00 [pmc-release] AID - S0021-9150(19)31369-3 [pii] AID - 10.1016/j.atherosclerosis.2019.06.901 [doi] PST - ppublish SO - Atherosclerosis. 2019 Aug;287:70-80. doi: 10.1016/j.atherosclerosis.2019.06.901. Epub 2019 Jun 13.