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Updated: Apr 6, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice
G Li1,2, C Chen1,2, S D Laing1,2
1Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Insights
Downregulating peroxisome proliferator-activated receptor delta (PPARδ) in hematopoietic stem cells reduced atherosclerosis in mice. This microRNA-mediated approach decreased inflammatory factors and lesion development, offering a potential gene therapy strategy.
Area of Science:
- Cardiovascular Research
- Immunology
- Gene Therapy
Background:
- Peroxisome proliferator-activated receptor delta (PPARδ) plays a role in lipid metabolism and inflammation.
- While PPARδ agonists can treat atherosclerosis, its role in hematopoietic cells is complex.
- Genetic deletion of PPARδ in hematopoietic cells reduced atherosclerosis in mouse models.
Purpose of the Study:
- To investigate the therapeutic potential of downregulating PPARδ in hematopoietic cells for atherosclerosis.
- To utilize microRNA (miRNA)-based gene therapy for PPARδ knockdown.
- To assess the impact of PPARδ reduction on atherosclerotic lesion development in mice.
Main Methods:
- Developed miRNA to knock down PPARδ expression in bone marrow cells.
- Transplanted modified cells into low-density lipoprotein receptor-deficient (LDLR-/-) mice.
- Analyzed aortic atherosclerotic lesions, macrophage infiltration, and inflammatory marker expression.
Main Results:
- PPARδ knockdown in hematopoietic cells significantly reduced aortic atherosclerotic lesions.
- Decreased expression of pro-inflammatory factors (MCP-1, IL-1β, IL-6) and CCR2 in macrophages.
- Reduced macrophage presence in lesions, associated with altered ABCA1 and adipocyte differentiation-related protein levels.
- Lowered MCP-1 and MMP-9 protein levels in atherosclerotic plaques.
Conclusions:
- MicroRNA-mediated knockdown of PPARδ in hematopoietic cells effectively ameliorates atherosclerosis.
- This approach reduces key inflammatory mediators and cellular components of atherosclerotic lesions.
- PPARδ targeting in hematopoietic stem cells presents a promising strategy for atherosclerosis gene therapy.
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.
