Abstract
Objective: We have previously shown that the transcription factor, nuclear factor of activated T-cells 5 (NFAT5), regulates vascular smooth muscle cell phenotypic modulation, but the role of NFAT5 in atherosclerosis is unknown. Our main objective was to determine if NFAT5 expression in bone marrow (BM)-derived cells altered atherosclerotic development and macrophage function. Methods and Results: NFAT5+/−ApoE−/− mice were generated for in vivo atherosclerosis studies. Following high fat diet feeding, en face analysis of the thoracic aorta established that genome-wide NFAT5 haploinsufficiency reduced atherosclerotic lesion formation by 73%. BM transplant studies revealed that transplantation of NFAT5+/−ApoE−/− marrow into NFAT5+/+ApoE−/− mice resulted in a similar 86% reduction in lesion formation. In vitro functional analysis of BM-derived macrophages demonstrated that NFAT5 is required for macrophage migration, which is a key event in the propagation of atherosclerosis. Conclusion: We have identified NFAT5 in BM-derived cells as a positive regulator of atherosclerotic lesion formation and macrophage function in the vasculature.
Highlights
Nuclear factor of activated T-cells 5 (NFAT5/tonicity-responsive enhancer binding protein) is a Rel homology transcription factor that is critical for the regulation of various cellular functions in both hypertonic and isotonic environments (Miyakawa et al, 1999; Woo et al, 2002; Halterman et al, 2011a)
We have previously shown that the transcription factor, nuclear factor of activated T-cells 5 (NFAT5), regulates vascular smooth muscle cell phenotypic modulation, but the role of NFAT5 in atherosclerosis is unknown
We show that bone marrow-derived macrophages (BMDMs) harvested from NFAT5+/− mice have impaired migratory abilities, and we believe these findings are noteworthy because macrophage migration into the lesion is a key event in the propagation of atherosclerosis
Summary
Nuclear factor of activated T-cells 5 (NFAT5/tonicity-responsive enhancer binding protein) is a Rel homology transcription factor that is critical for the regulation of various cellular functions in both hypertonic and isotonic environments (Miyakawa et al, 1999; Woo et al, 2002; Halterman et al, 2011a). In tissues that do not undergo large fluctuations in tonicity such as the vasculature, rheumatoid arthritic joints, and carcinomas, various tonicity-independent stimuli have been identified as regulating NFAT5 expression and activity (Jauliac et al, 2002; Yoon et al, 2011; Halterman et al, 2011b). Previous studies in our lab were the first to describe NFAT5 function in the vasculature, and our research has identified a hypertonicity-independent role for NFAT5 in vascular smooth muscle cell (SMC) phenotypic modulation (Halterman et al, 2011b). The role of NFAT5 in chronic atherosclerotic vascular disease is unknown
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