PMID- 26204499 OWN - NLM STAT- MEDLINE DCOM- 20161006 LR - 20181113 IS - 1476-5462 (Electronic) IS - 0969-7128 (Print) IS - 0969-7128 (Linking) VI - 23 IP - 1 DP - 2016 Jan TI - Hematopoietic knockdown of PPARdelta reduces atherosclerosis in LDLR-/- mice. PG - 78-85 LID - 10.1038/gt.2015.78 [doi] AB - PPARdelta (peroxisome proliferator-activated receptor delta) mediates inflammation in response to lipid accumulation. Systemic administration of a PPARdelta agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPARdelta in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPARdelta 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 PPARdelta expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPARdelta expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPARdelta led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1beta 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 PPARdelta knockdown in hematopoietic cells is able to ameliorate atherosclerosis. FAU - Li, G AU - Li G AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. FAU - Chen, C AU - Chen C AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. FAU - Laing, S D AU - Laing SD AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. FAU - Ballard, C AU - Ballard C AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. FAU - Biju, K C AU - Biju KC AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. FAU - Reddick, R L AU - Reddick RL AD - Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA. FAU - Clark, R A AU - Clark RA AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. FAU - Li, S AU - Li S AD - Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. AD - Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. AD - Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA. LA - eng GR - F30 DE023285/DE/NIDCR NIH HHS/United States GR - I01 BX000737/BX/BLRD VA/United States GR - UL1 TR001120/TR/NCATS NIH HHS/United States GR - TR001120/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20150823 PL - England TA - Gene Ther JT - Gene therapy JID - 9421525 RN - 0 (ABCA1 protein, mouse) RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (MicroRNAs) RN - 0 (PPAR delta) RN - 0 (Receptors, CCR2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) SB - IM MH - ATP Binding Cassette Transporter 1/genetics/metabolism MH - Animals MH - Aorta/pathology MH - Atherosclerosis/*genetics/prevention & control MH - Chemokine CCL2/genetics/metabolism MH - Down-Regulation MH - Female MH - Gene Expression Regulation MH - Gene Knockdown Techniques MH - Genetic Therapy/*methods MH - Hematopoietic Stem Cells/cytology/metabolism MH - Interleukin-1beta/genetics/metabolism MH - Interleukin-6/genetics/metabolism MH - Macrophages/metabolism MH - Matrix Metalloproteinase 9/genetics/metabolism MH - Mice MH - Mice, Knockout MH - MicroRNAs/genetics/metabolism MH - PPAR delta/*genetics/metabolism MH - Plaque, Atherosclerotic/genetics/pathology MH - Receptors, CCR2/genetics/metabolism PMC - PMC4939901 MID - NIHMS798023 COIS- CONFLICT OF INTEREST The authors declare no conflict of interest. EDAT- 2015/07/24 06:00 MHDA- 2016/10/08 06:00 PMCR- 2016/07/11 CRDT- 2015/07/24 06:00 PHST- 2014/12/09 00:00 [received] PHST- 2015/06/01 00:00 [revised] PHST- 2015/07/08 00:00 [accepted] PHST- 2015/07/24 06:00 [entrez] PHST- 2015/07/24 06:00 [pubmed] PHST- 2016/10/08 06:00 [medline] PHST- 2016/07/11 00:00 [pmc-release] AID - gt201578 [pii] AID - 10.1038/gt.2015.78 [doi] PST - ppublish SO - Gene Ther. 2016 Jan;23(1):78-85. doi: 10.1038/gt.2015.78. Epub 2015 Aug 23.