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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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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Peroxisome Proliferator-Activated Receptors
Atherosclerosis
Chemokine CCL2
MicroRNAs
Down-Regulation
CCR2 Receptors
Macrophages
Hematopoietic System
Hematopoietic Stem Cell Transplantation
Matrix Metalloproteinase 9
Bone Marrow Transplantation
Interleukin-1
Adipocytes
Genetic Therapy
Interleukin-6
Proteins
Adenosine Triphosphate
Inflammation
Lipids

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Li, G., Chen, C., Laing, S. D., Ballard, C., Biju, K. C., Reddick, R. L., ... Li, S. (2016). Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice. Gene Therapy, 23(1), 78-85. https://doi.org/10.1038/gt.2015.78

Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice. / Li, G.; Chen, C.; Laing, S. D.; Ballard, C.; Biju, K. C.; Reddick, R. L.; Clark, Robert A; Li, Senlin.

In: Gene Therapy, Vol. 23, No. 1, 01.01.2016, p. 78-85.

Research output: Contribution to journalArticle

Li, G, Chen, C, Laing, SD, Ballard, C, Biju, KC, Reddick, RL, Clark, RA & Li, S 2016, 'Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice', Gene Therapy, vol. 23, no. 1, pp. 78-85. https://doi.org/10.1038/gt.2015.78
Li G, Chen C, Laing SD, Ballard C, Biju KC, Reddick RL et al. Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice. Gene Therapy. 2016 Jan 1;23(1):78-85. https://doi.org/10.1038/gt.2015.78
Li, G. ; Chen, C. ; Laing, S. D. ; Ballard, C. ; Biju, K. C. ; Reddick, R. L. ; Clark, Robert A ; Li, Senlin. / Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice. In: Gene Therapy. 2016 ; Vol. 23, No. 1. pp. 78-85.
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