Abstract
The roles of myocardin-related transcription factor A (MRTF-A) and MRTF-B in vascular endothelial cells are not completely understood. Here, we found a novel regulatory mechanism for MRTF-A/B function. MRTF-A/B tend to accumulate in the nucleus in arterial endothelial cells in vivo and human aortic endothelial cells (HAoECs) in vitro. In HAoECs, nuclear localization of MRTF-A/B was not significantly affected by Y27632 or latrunculin B, primarily due to the reduced binding of MRTF-A/B to G-actin and in part, to the low level of MRTF-A phosphorylation by ERK. MRTF-A/B downregulation by serum depletion or transfection of siRNA against MRTF-A and/or MRTF-B induced ICAM-1 expression in HAoECs. It is known that nuclear import of nuclear factor−κB (NF−κB) plays a key role in ICAM-1 gene transcription. However, nuclear accumulation of NF−κB p65 was not observed in MRTF-A/B-depleted HAoECs. Our present findings suggest that MRTF-A/B inhibit ICAM-1 mRNA expression by forming a complex with NF−κB p65 in the nucleus. Conversely, downregulation of MRTF-A/B alleviates this negative regulation without further translocation of NF−κB p65 into the nucleus. These results reveal the novel roles of MRTF-A/B in the homeostasis of vascular endothelium.
Highlights
Myocardin-related transcription factor A (MRTF-A) and MRTF-B are members of the myocardin family of transcriptional coactivators that activate serum response factor (SRF)[1] and Smad[2,3]
Our present findings are schematically summarized in Fig. 7; myocardin-related transcription factor A (MRTF-A)/B tend to accumulate in the nucleus because of their reduced binding to G-actin and play a critical role in maintaining the homeostasis of vascular endothelium
MRTF-A expression levels significantly increased after stimulation with oxidatively modified low-density lipoprotein (oxLDL) or transforming growth factor− β, and nuclear accumulation of MRTF-A is concomitantly enhanced with an increase in MRTF-A expression
Summary
Myocardin-related transcription factor A (MRTF-A) and MRTF-B are members of the myocardin family of transcriptional coactivators that activate serum response factor (SRF)[1] and Smad[2,3]. ERK activation is reduced because Rho pathways are constitutively activated by loss of a tumor suppressor Deleted in Liver Cancer[17] In these cells, MRTF-A is constitutively localized in the nucleus, resulting in the activation of cell migration and proliferation. Vascular endothelial cells overexpress inflammatory cytokines, chemokines such as monocyte chemoattractant protein-1, and adhesion molecules such as intercellular adhesion molecular-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)[20]. These responses are mediated by activation of nuclear factor− κ B (NF− κ B), a key transcription factor for inflammatory responses[21]
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