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 language | English (US) |
|---|---|
| Pages (from-to) | 78-85 |
| Number of pages | 8 |
| Journal | Gene Therapy |
| Volume | 23 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
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ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
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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 journal › Article
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TY - JOUR
T1 - Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice
AU - Li, G.
AU - Chen, C.
AU - Laing, S. D.
AU - Ballard, C.
AU - Biju, K. C.
AU - Reddick, R. L.
AU - Clark, Robert A
AU - Li, Senlin
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/gt.2015.78
DO - 10.1038/gt.2015.78
M3 - Article
VL - 23
SP - 78
EP - 85
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
IS - 1
ER -