PMID- 22628578 OWN - NLM STAT- MEDLINE DCOM- 20120828 LR - 20220311 IS - 1524-4571 (Electronic) IS - 0009-7330 (Print) IS - 0009-7330 (Linking) VI - 111 IP - 1 DP - 2012 Jun 22 TI - Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/CBS-deficient mice. PG - 37-49 LID - 10.1161/CIRCRESAHA.112.269472 [doi] AB - RATIONALE: Hyperhomocysteinemia (HHcy) accelerates atherosclerosis and increases inflammatory monocytes (MC) in peripheral tissues. However, its causative role in atherosclerosis is not well established and its effect on vascular inflammation has not been studied. The underlying mechanism is unknown. OBJECTIVE: This study examined the causative role of HHcy in atherogenesis and its effect on inflammatory MC differentiation. METHODS AND RESULTS: We generated a novel HHcy and hyperlipidemia mouse model, in which cystathionine beta-synthase (CBS) and low-density lipoprotein receptor (LDLr) genes were deficient (Ldlr(-/-) Cbs(-/+)). Severe HHcy (plasma homocysteine (Hcy)=275 mumol/L) was induced by a high methionine diet containing sufficient basal levels of B vitamins. Plasma Hcy levels were lowered to 46 mumol/L from 244 mumol/L by vitamin supplementation, which elevated plasma folate levels. Bone marrow (BM)-derived cells were traced by the transplantation of BM cells from enhanced green fluorescent protein (EGFP) transgenic mice after sublethal irradiation of the recipient. HHcy accelerated atherosclerosis and promoted Ly6C(high) inflammatory MC differentiation of both BM and tissue origins in the aortas and peripheral tissues. It also elevated plasma levels of TNF-alpha, IL-6, and MCP-1; increased vessel wall MC accumulation; and increased macrophage maturation. Hcy-lowering therapy reversed HHcy-induced lesion formation, plasma cytokine increase, and blood and vessel inflammatory MC (Ly6C(high+middle)) accumulation. Plasma Hcy levels were positively correlated with plasma levels of proinflammatory cytokines. In primary mouse splenocytes, L-Hcy promoted rIFNgamma-induced inflammatory MC differentiation, as well as increased TNF-alpha, IL-6, and superoxide anion production in inflammatory MC subsets. Antioxidants and folic acid reversed L-Hcy-induced inflammatory MC differentiation and oxidative stress in inflammatory MC subsets. CONCLUSIONS: HHcy causes vessel wall inflammatory MC differentiation and macrophage maturation of both BM and tissue origins, leading to atherosclerosis via an oxidative stress-related mechanism. FAU - Zhang, Daqing AU - Zhang D AD - Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. FAU - Fang, Pu AU - Fang P FAU - Jiang, Xiaohua AU - Jiang X FAU - Nelson, Jun AU - Nelson J FAU - Moore, Jodene K AU - Moore JK FAU - Kruger, Warren D AU - Kruger WD FAU - Berretta, Remus M AU - Berretta RM FAU - Houser, Steven R AU - Houser SR FAU - Yang, Xiaofeng AU - Yang X FAU - Wang, Hong AU - Wang H LA - eng GR - HL82774/HL/NHLBI NIH HHS/United States GR - R01 HL108910/HL/NHLBI NIH HHS/United States GR - R01 HL077288/HL/NHLBI NIH HHS/United States GR - HL108910/HL/NHLBI NIH HHS/United States GR - HL77288/HL/NHLBI NIH HHS/United States GR - HL67033/HL/NHLBI NIH HHS/United States GR - R01 HL082774/HL/NHLBI NIH HHS/United States GR - HL57299/HL/NHLBI NIH HHS/United States GR - HL11076/HL/NHLBI NIH HHS/United States GR - R01 HL094451/HL/NHLBI NIH HHS/United States GR - HL94451/HL/NHLBI NIH HHS/United States GR - R01 HL057299/HL/NHLBI NIH HHS/United States GR - R01 HL067033/HL/NHLBI NIH HHS/United States GR - R01 HL110764/HL/NHLBI NIH HHS/United States GR - R29 HL057299/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20120524 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (Antioxidants) RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-6) RN - 0 (Lipids) RN - 0 (Receptors, LDL) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (enhanced green fluorescent protein) RN - 11062-77-4 (Superoxides) RN - 12001-76-2 (Vitamin B Complex) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 4.- (Lyases) RN - EC 4.4.1.8 (cystathionine beta-lyase) SB - IM MH - Animals MH - Antioxidants/pharmacology MH - Aorta/drug effects/*enzymology/immunology/pathology MH - Atherosclerosis/blood/enzymology/*etiology/genetics/pathology MH - Bone Marrow Cells/drug effects/*enzymology/immunology MH - Bone Marrow Transplantation MH - *Cell Differentiation MH - Cells, Cultured MH - Chemokine CCL2/blood MH - Disease Models, Animal MH - Green Fluorescent Proteins/biosynthesis/genetics MH - Hyperhomocysteinemia/blood/*complications/enzymology/genetics/immunology MH - Hyperlipidemias/complications/enzymology/immunology MH - Inflammation/blood/enzymology/*etiology/immunology MH - Inflammation Mediators/blood MH - Interleukin-6/blood MH - Lipids/blood MH - Lyases/*deficiency/genetics MH - Macrophages/drug effects/*enzymology/immunology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Oxidative Stress MH - Receptors, LDL/*deficiency/genetics MH - Severity of Illness Index MH - Superoxides/metabolism MH - Tumor Necrosis Factor-alpha/blood MH - Vitamin B Complex/pharmacology PMC - PMC3412115 MID - NIHMS386879 COIS- Conflict-of interest; none EDAT- 2012/05/26 06:00 MHDA- 2012/08/29 06:00 PMCR- 2013/06/22 CRDT- 2012/05/26 06:00 PHST- 2012/05/26 06:00 [entrez] PHST- 2012/05/26 06:00 [pubmed] PHST- 2012/08/29 06:00 [medline] PHST- 2013/06/22 00:00 [pmc-release] AID - CIRCRESAHA.112.269472 [pii] AID - 10.1161/CIRCRESAHA.112.269472 [doi] PST - ppublish SO - Circ Res. 2012 Jun 22;111(1):37-49. doi: 10.1161/CIRCRESAHA.112.269472. Epub 2012 May 24.