title: Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice.
abstract: PPARδ (peroxisome proliferator-activated receptor δ) mediates inflammation in response to lipid accumulation. Systemic administration of a PPARδ agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPARδ in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPARδ expression in these cells may mitigate atherogenesis. To advance this finding forward to potential clinical translation through hematopoietic stem cell transplantation-based gene therapy, we employed a microRNA (miRNA) approach to knock down PPARδ expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPARδ expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPARδ led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β and IL-6. Expression of CCR2, a receptor for MCP-1, was also decreased. The downregulation of pro-inflammatory factors is consistent with significant reduction of macrophage presence in the lesions, which may also be attributable to elevation of ABCA1 (ATP-binding cassette, subfamily A, member 1) and depression of adipocyte differentiate-related protein. Furthermore, the abundance of both MCP-1 and matrix metalloproteinase-9 proteins was reduced in plaque areas. Our results demonstrate that miRNA-mediated PPARδ knockdown in hematopoietic cells is able to ameliorate atherosclerosis.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Laing
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ballard
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Biju
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Reddick
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Clark
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA.|Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics* / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D015850:Interleukin-6; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D047494:PPAR delta; D054390:Receptors, CCR2; C577833:Abca1 protein, mouse; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; C501830:Mmp9 protein, mouse