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Atherosclerosis development is differentially regulated in whole genome vs. bone marrow‐derived haploinsufficient NFAT5/ApoE null mice
Author(s) -
Halterman Julia Ann,
Kwon H Moo,
Wamhoff Brian R
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.681.1
Subject(s) - lesion , haploinsufficiency , apolipoprotein e , bone marrow , biology , pathology , immunohistochemistry , aorta , myeloid , phenotype , cancer research , medicine , immunology , gene , genetics , disease
We have previously shown that the transcription factor, nuclear factor of activated T‐cells 5 (NFAT5), plays a role in vascular smooth muscle cell phenotypic modulation in acute injury, but the role of NFAT5 in atherosclerosis is unknown. Our main objectives were to determine if genome‐wide NFAT5 haploinsufficency (NFAT5+/−) altered atherosclerotic development and to determine whether NFAT5 expression in bone marrow (BM)‐derived cells affected lesion progression. NFAT5+/−ApoE−/− mice were placed on a high fat diet for 20 wks and analysis of the thoracic aorta and aortic arch established that genome‐wide NFAT5 haploinsufficiency reduced atherosclerotic lesion formation by 73% and 43%, respectively, but did not alter lesion size in the aortic root. BM transplant studies revealed that transplantation of NFAT5+/−ApoE−/− BM into NFAT5+/+ApoE−/− mice resulted in a similar 86% reduction in lesion formation of the thoracic aorta, yet produced an unexpected 37% increase in total lesion area of the aortic root. Immunohistochemical analysis of root lesions revealed that mice transplanted with NFAT5‐deficient BM had increased macrophage investment of the lesion. We have identified that NFAT5 expression in BM‐derived cells is critical for the regulation of lesion morphometry and composition, and we show that NFAT5 deficiency in macrophages leads to their increased investment of aortic root lesions.