Nuclear Factor of Activated T Cells 5 Regulates Vascular Smooth Muscle Cell Phenotypic Modulation

作者：Halterman Julia A; Kwon H Moo; Zargham Ramin; Bortz Pamela D Schoppee; Wamhoff Brian R^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(10): 2287-U317.

DOI：10.1161/ATVBAHA.111.232165

• angiotensin II
• growth factors
• NFAT5
• phenotypic modulation
• smooth muscle

Objective-The tonicity-responsive transcription factor, nuclear factor of activated T cells 5 (NFAT5/tonicity enhancer binding protein [TonEBP]), has been well characterized in numerous cell types; however, NFAT5 function in vascular smooth muscle cells (SMCs) is unknown. Our main objective was to determine the role of NFAT5 regulation in SMCs.
Methods and Results-We showed that NFAT5 is regulated by hypertonicity in SMCs and is upregulated in atherosclerosis and neointimal hyperplasia. RNAi knockdown of NFAT5 inhibited basal expression of several SMC differentiation marker genes, including smooth muscle alpha actin (SM alpha A). Bioinformatic analysis of SM alpha A revealed 7 putative NFAT5 binding sites in the first intron, and chromatin immunoprecipitation analysis showed NFAT5 enrichment of intronic DNA. Overexpression of NFAT5 increased SM alpha A promoter-intron activity, which requires an NFAT5 cis element at +1012, whereas dominant-negative NFAT5 decreased SM alpha A promoter-intron activity. Because it is unlikely that SMCs experience extreme changes in tonicity, we investigated other stimuli and uncovered 2 novel NFAT5-inducing factors: angiotensin II, a contractile agonist, and platelet-derived growth factor-BB (PDGF-BB), a potent mitogen in vascular injury. Angiotensin II stimulated NFAT5 translocation and activity, and NFAT5 knockdown inhibited an angiotensin II-mediated upregulation of SM alpha A mRNA. PDGF-BB increased NFAT5 protein, and loss of NFAT5 inhibited PDGF-BB-induced SMC migration.
Conclusion-We have identified NFAT5 as a novel regulator of SMC phenotypic modulation and have uncovered the role of NFAT5 in angiotensin II-induced SM alpha A expression and PDGF-BB-stimulated SMC migration. (Arterioscler Thromb Vasc Biol. 2011;31:2287-2296.)

• 出版日期2011-10