Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice

G. Li, C. Chen, S. D. Laing, C. Ballard, K. C. Biju, R. L. Reddick, R. A. Clark, S. Li

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

PPAR δ (peroxisome proliferator-activated receptor δ) mediates inflammation in response to lipid accumulation. Systemic administration of a PPAR δ agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPAR δ in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPAR δ 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 PPAR δ expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPAR δ expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPAR δ 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 PPAR δ knockdown in hematopoietic cells is able to ameliorate atherosclerosis.

Original languageEnglish (US)
Pages (from-to)78-85
Number of pages8
JournalGene Therapy
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2016

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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