title: Mesenchymal Stem Cells Ameliorate Atherosclerotic Lesions via Restoring Endothelial Function.
abstract: Transplantation of mesenchymal stem cells (MSCs) is beneficial in myocardial infarction and hind limb ischemia, but its ability to ameliorate atherosclerosis remains unknown. Here, the effects of MSCs on inhibiting endothelial dysfunction and atherosclerosis were investigated in human/mouse endothelial cells treated with oxidized low-density lipoprotein (oxLDL) and in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. Treatment with oxLDL inactivated the Akt/endothelial nitric-oxide synthase (eNOS) pathway, induced eNOS degradation, and inhibited nitric oxide (NO) production in endothelial cells. Coculture with human MSCs reversed the effects of oxLDL on endothelial cells and restored Akt/eNOS activity, eNOS level, and NO production. Reduction of endothelium-dependent relaxation and subsequent plaque formation were developed in apoE-/- mice fed a high-fat diet. Systemic infusion with mouse MSCs ameliorated endothelial dysfunction and plaque formation in high-fat diet-fed apoE-/- mice. Interestingly, treatment with interleukin-8 (IL8)/macrophage inflammatory protein-2 (MIP-2) alone induced the similar effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Neutralization antibodies (Abs) against IL8/MIP-2 also blocked the effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Consistently, MIP-2 injection alone induced the similar effect of MSCs on the endothelial function in high-fat diet-fed apoE-/- mice. The improvement in endothelial dysfunction by mouse MSCs was also blocked when pretreating MSCs with anti-MIP-2 Abs. In conclusion, MSC transplantation improved endothelial function and plaque formation in high-fat diet-fed apoE-/- mice. Activation of the Akt/eNOS pathway in endothelium by IL8/MIP-2 is involved in the protective effect of MSCs. The study helps support the use and clarify the mechanism of MSCs for ameliorating atherosclerosis.
authors.affiliation: Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China.
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.affiliation: Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China.
authors.forename: Yuan-Tong
authors.initials: YT
authors.lastname: Hsu
authors.affiliation: Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China hungsc@vghtpe.gov.tw jennyw355@gmail.com.
authors.forename: Guei-Jane
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: Institutes of Clinical Medicine, Pharmacology, and Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China; Stem Cell Laboratory, Department of Medical Research and Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China; Department of Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, Taiwan, Republic of China; Taiwan Bio Therapeutics, Taipei, Taiwan, Republic of China hungsc@vghtpe.gov.tw jennyw355@gmail.com.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
keywords: Apolipoprotein E-deficient; Atherosclerosis; Endothelial nitric-oxide synthase; Human umbilical vein endothelial cells; Interleukin-8; MIP-2; Mesenchymal stem cells (MSCs); Oxidized LDL; p38 MAPK pathway