Abstract-Modulation of smooth muscle cell (SMC) phenotype plays a central role in neointima formation. We recently demonstrated that Am80, a synthetic retinoic acid receptor ␣-specific agonist, inhibits the activity of the transcription factor KLF5, which is essential for neointima formation after vascular injury. In the present study, we aimed to further analyze the mechanism by which Am80 inhibits KLF5 and the effects of inhibiting KLF5 on SMCs and vascular lesion formation, as well as to evaluate potential of Am80 for use in the prevention of in-stent neointima formation. We found that Am80 inhibited both the expression and transcriptional function of KLF5. Of particular interest was our finding that KLF5 forms a transcriptionally active complex with unliganded RAR/RXR heterodimer on the PDGF-A promoter; Am80 disrupts this complex, thereby inhibiting KLF5-dependent transcriptional activation. Knocking down KLF5 using small interfering RNA suppressed serum-induced downregulation of SMC differentiation marker gene expression in cultured SMCs, and haploinsufficiency of KLF5 in mice attenuated phenotypic modulation of SMCs after vascular injury, indicating that KLF5 plays a key role in the control of SMC phenotype. Am80 augmented expression of the SMC differentiation marker genes in culture and within the vessel walls, and oral administration of Am80 significantly inhibited in-stent neointima formation in a rabbit stent-placement model. Taken together, these results demonstrate that KLF5 plays an important role in the control of SMC phenotype after vascular injury and suggest the feasibility of using Am80, delivered systemically and/or with a drug eluting stent, to prevent in-stent neointima formation. (Circ Res. 2005;97:1132-1141.)Key Words: stent Ⅲ smooth muscle Ⅲ restenosis Ⅲ retinoid Ⅲ phenotypic modulation T he neointima that forms after percutaneous coronary intervention (PCI) is mainly composed of smooth muscle cells (SMCs) and the extracellular matrix they produce. 1 In response to external stresses such as mechanochemical stress, the effects of various humoral factors, and direct interaction with inflammatory cells, SMCs undergo phenotypic modulation. These phenotypically modulated SMCs proliferate, migrate, and produce various paracrine factors, extracellular matrix, and matrix proteases, thereby promoting the remodeling of the vascular wall. 2,3 Consequently, SMCs are considered to be one of the most important targets of therapies aimed at preventing restenosis.We recently showed that the Krüppel-like transcription factor KLF5 mediates stress-induced vascular remodeling, and that haploinsufficiency of KLF5 in KLF5 ϩ/Ϫ mice much reduces neointima formation in vascular injury models. 4 Moreover, we identified a novel synthetic retinoid, Am80, to be a potent inhibitor of KLF5. 4 Am80 is a retinoic acid receptor (RAR) ␣-specific agonist that has been safely used to treat acute promyelocytic leukemia. As expected from its in vitro inhibitory effects on KLF5, Am80 inhibited neointima formation in a mous...

Abstract:Superconductors with persistent zero-resistance currents serve as permanent magnets for high-field applications requiring a strong and stable magnetic field, such as magnetic resonance imaging (MRI). The recent global helium shortage has quickened research into high-temperature superconductors (HTSs)-materials that can be used without conventional liquid-helium cooling to 4.2 K. Herein, we demonstrate that 40-K-class metallic HTS magnesium diboride (MgB 2 ) makes an excellent permanent bulk magnet, maintaining 3 T at 20 K for 1 week with an extremely high stability (<0.1 ppm/h). The magnetic field trapped in this magnet is uniformly distributed, as for single-crystalline neodymium-iron-boron. Magnetic hysteresis loop of the MgB 2 permanent bulk magnet was detrmined. Because MgB 2 is a simple-binary-line compound that does not contain rare-earth metals, polycrystalline bulk material can be industrially fabricated at low cost and with high yield to serve as strong magnets that are compatible with conventional compact cryocoolers, making MgB 2 bulks promising for the next generation of Tesla-class permanent-magnet applications.

Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the