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Nuclear factor of activated T‐cells 5 (NFAT5) regulates vascular smooth muscle cell phenotypic modulation and enhances atherosclerotic plaque development
Author(s) -
Halterman Julia Ann,
Kwon H Moo,
Wamhoff Brian R
Publication year - 2011
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.25.1_supplement.1026.29
Subject(s) - gene knockdown , vascular smooth muscle , calponin , serum response factor , microbiology and biotechnology , biology , growth factor , transcription factor , downregulation and upregulation , chemistry , regulator , endocrinology , medicine , cancer research , gene , actin , receptor , biochemistry , smooth muscle
Nuclear factor of activated T‐cells 5 (NFAT5) is a tonicity‐responsive transcription factor; however, NFAT5 function in vascular smooth muscle cells (SMCs) is unknown. We have identified NFAT5 as a positive regulator of both the contractile, and paradoxically, the synthetic SMC phenotypes. RNAi‐mediated knockdown of NFAT5 inhibits basal expression levels of classic SMC‐specific contractile genes (i.e. SMαA, Calponin, Smoothelin, SM22α), as well as genes involved in SMC migration and injury (i.e. Cyr61, VEGF‐C, COX2). We have identified Ang II, a contractile agonist, and PDGF‐BB, a growth factor released in vascular injury, as two novel NFAT5‐stimulating factors. Ang II‐induced SMαA promoter activity and RNA expression is attenuated following endogenous NFAT5 knockdown, and unstimulated NFAT5 null mouse embryonic fibroblasts have a 97% reduction in SMαA expression. In addition, both PDGF‐BB and serum‐mediated SMC migration are NFAT5‐dependent. In vivo injury data show NFAT5 is upregulated following rat carotid balloon injury and in the ApoE−/− atherosclerotic plaque. Remarkably, haploinsufficient NFAT5+/−ApoE−/− mice have a 73% reduction in atherosclerotic plaque formation in the descending aorta. In conclusion, we have identified NFAT5 as a novel regulator of both the contractile and synthetic SMC phenotypes and give evidence to its important role in the development of atherosclerosis.