PMID- 34852642 OWN - NLM STAT- MEDLINE DCOM- 20220217 LR - 20230513 IS - 1524-4636 (Electronic) IS - 1079-5642 (Print) IS - 1079-5642 (Linking) VI - 42 IP - 2 DP - 2022 Feb TI - Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice. PG - 113-126 LID - 10.1161/ATVBAHA.121.316090 [doi] AB - OBJECTIVE: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe(-/)(-) (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe(-)(/)(-) background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1-derived peritoneal macrophages. CONCLUSIONS: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux. FAU - Snarski, Patricia AU - Snarski P AUID- ORCID: 0000-0002-2470-7655 AD - Section of Cardiology, John W. Deming Department of Medicine (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Physiology (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. FAU - Sukhanov, Sergiy AU - Sukhanov S AD - Section of Cardiology, John W. Deming Department of Medicine (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Physiology (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. FAU - Yoshida, Tadashi AU - Yoshida T AD - Section of Cardiology, John W. Deming Department of Medicine (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Physiology (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. FAU - Higashi, Yusuke AU - Higashi Y AD - Section of Cardiology, John W. Deming Department of Medicine (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Physiology (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. FAU - Danchuk, Svitlana AU - Danchuk S AD - Section of Cardiology, John W. Deming Department of Medicine (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Physiology (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. FAU - Chandrasekar, Bysani AU - Chandrasekar B AUID- ORCID: 0000-0002-8212-5354 AD - Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (B.C.). AD - Department of Medical Pharmacology and Physiology, University of Missouri, Columbia (B.C.). FAU - Tian, Di AU - Tian D AUID- ORCID: 0000-0002-6879-6629 AD - Department of Pathology (D.T.), Tulane University School of Medicine, New Orleans, LA. FAU - Rivera-Lopez, Vikara AU - Rivera-Lopez V AD - Loyola University, New Orleans, LA (V.R.-L.). FAU - Delafontaine, Patrick AU - Delafontaine P AUID- ORCID: 0000-0003-3744-3617 AD - Section of Cardiology, John W. Deming Department of Medicine (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Physiology (P.S., S.S., T.Y., Y.H., S.D., P.D.), Tulane University School of Medicine, New Orleans, LA. AD - Department of Pharmacology (P.D.), Tulane University School of Medicine, New Orleans, LA. LA - eng GR - I01 BX005845/BX/BLRD VA/United States GR - IK6 BX004016/BX/BLRD VA/United States GR - R01 HL070241/HL/NHLBI NIH HHS/United States GR - R01 HL142796/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211202 PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 RN - 0 (Apolipoproteins E) RN - 0 (Chemokine CXCL12) RN - 0 (Cxcl12 protein, mouse) RN - 0 (insulin-like growth factor-1, rat) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Animals MH - Apolipoproteins E/*genetics MH - Atherosclerosis/blood/*genetics/pathology MH - Chemokine CXCL12/analysis/*blood MH - Female MH - Gene Deletion MH - Humans MH - Insulin-Like Growth Factor I/*genetics MH - Macrophages/*metabolism MH - Male MH - Mice MH - Mice, Knockout MH - Rats MH - THP-1 Cells MH - Up-Regulation PMC - PMC8792341 MID - NIHMS1759459 OTO - NOTNLM OT - atherosclerosis OT - cytokines OT - inflammation OT - intercellular signaling peptides and proteins OT - lipids EDAT- 2021/12/03 06:00 MHDA- 2022/02/19 06:00 PMCR- 2023/02/01 CRDT- 2021/12/02 05:29 PHST- 2021/12/03 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2021/12/02 05:29 [entrez] PHST- 2023/02/01 00:00 [pmc-release] AID - 10.1161/ATVBAHA.121.316090 [doi] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2022 Feb;42(2):113-126. doi: 10.1161/ATVBAHA.121.316090. Epub 2021 Dec 2.