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

PPAR(delta) (peroxisome proliferator-activated receptor delta) mediates inflammation in response to lipid accumulation. Systemic administration of a PPAR(delta) agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPAR(delta) in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPAR(delta) 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(delta) expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPARd expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPAR(delta) led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1 beta 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 delta knockdown in hematopoietic cells is able to ameliorate atherosclerosis.