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ABSTRACT: Sulforaphane, a naturally occurring organosulfur compound in broccoli, has chemopreventive properties in cancer. However, the effects of sulforaphane in vascular diseases have not been examined. We therefore aimed to investigate the effects of sulforaphane on vascular smooth muscle cell (VSMC) proliferation and neointimal formation and the related mechanisms.
The expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) was examined in VSMCs. The nuclear translocation of nuclear factor-κB (NF-κB) and GATA6 expression was examined in VSMCs and in a carotid artery injury model by Western blot and immunohistochemistry. We also investigated whether local delivery of sulforaphane affected neointimal formation.
Sulforaphane inhibited the mRNA and protein expression of VCAM-1 induced by tumor necrosis factor (TNF)-α in VSMCs. Treatment of VSMCs with sulforaphane blocked TNF-α-induced IκBα degradation and NF-κB p65 and GATA6 expression. Furthermore, NF-κB p65 and GATA6 expression were reduced in sulforaphane-treated carotid injury sections. Notably, binding of GATA6 to the VCAM-1 promoter was dramatically reduced by sulforaphane. The MTT, BrdU incorporation, and in vitro scratch assays revealed that the proliferation and migration of VSMCs were reduced by sulforaphane. Furthermore, local administration of sulforaphane significantly reduced neointima formation 14 days after vascular injury in rats.
Our results indicate that sulforaphane inhibits neointima formation via targeting of adhesion molecules through the suppression of NF-κB/GATA6. Furthermore, sulforaphane regulates migration and proliferation in VSMCs. Sulforaphane may be a potential therapeutic agent for preventing restenosis after vascular injury.
Atherosclerosis 08/2012; 225(1):41-9. · 3.79 Impact Factor
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ABSTRACT: Previously, we reported that enhancer of polycomb1 (Epc1) induces skeletal muscle differentiation through the serum response factor (SRF). Considering that SRF plays a critical role in vascular smooth muscle cell (VSMC) differentiation, we expected that Epc1 also works in VSMCs. Here we examined the effect of Epc1 on neointima formation after arterial balloon injury and the underlying mechanism.
Epc1 expression was examined in carotid artery injury or VSMC models. Interaction with myocardin (Myocd), a master regulator of smooth muscle differentiation, was examined by immunoprecipitation or promoter analysis with smooth muscle (SM) 22α promoter. Finally, we investigated whether local delivery of Epc1 regulated neointimal formation after injury.
Epc1 expression was down-regulated during proliferation induced by platelet-derived growth factor BB, whereas it was upregulated during differentiation in VSMCs. Forced expression of Epc1 induced VSMC differentiation. Epc1 physically interacted with Myocd to synergistically activate SM22α promoter activity. Transient transfection of Epc1 enhanced the physical interaction between Myocd and SRF, whereas that interaction was reduced when A10 cells were treated with siRNA for Epc1. Local delivery of Epc1 significantly reduced neointima formation induced by balloon injury.
Our results indicate that Epc1 induces VSMC differentiation by interacting with Myocd to induce SRF-dependent smooth muscle genes. We propose that Epc1 acts as a novel negative regulator of neointima formation after carotid injury.
Atherosclerosis 02/2012; 222(1):84-91. · 3.79 Impact Factor
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Gwang Hyeon Eom,
Young Kuk Cho,
Jeong-Hyeon Ko,
Sera Shin,
Nakwon Choe,
Yoojung Kim, Hosouk Joung,
Hyung-Seok Kim,
Kwang-Il Nam,
Hae Jin Kee,
Hyun Kook
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ABSTRACT: Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone deacetylases (HDACs) are tightly linked to the regulation of those genes. We previously demonstrated that activation of HDAC2, 1 of the class I HDACs, mediates hypertrophy. Here, we show that casein kinase-2α1 (CK2α1)-dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy.
Hypertrophic stimuli phosphorylated HDAC2 S394, which was necessary for its enzymatic activation, and therefore the development of hypertrophic phenotypes in rat neonatal cardiomyocytes or in isoproterenol-administered mice hearts. Transgenic mice overexpressing HDAC2 wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant HDAC2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of HDAC2 S394 was dramatically increased in patients with hypertrophic cardiomyopathy. Hypertrophy-induced phosphorylation of HDAC2 S394 and its enzymatic activity were completely blocked either by CK2 blockers or by CK2α1 short interfering RNA. Hypertrophic stimuli led CK2α1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2α1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2α1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2α1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2α1-transgenic mice were crossed with HDAC2 S394A-transgenic mice.
We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394.
Circulation 05/2011; 123(21):2392-403. · 14.74 Impact Factor
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Ju-Ryoung Kim,
Hae Jin Kee,
Ji-Young Kim, Hosouk Joung,
Kwang-Il Nam,
Gwang Hyeon Eom,
Nakwon Choe,
Hyung-Suk Kim,
Jeong Chul Kim,
Hoon Kook,
Sang Beom Seo,
Hyun Kook
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ABSTRACT: Skeletal muscle differentiation is well regulated by a series of transcription factors. We reported previously that enhancer of polycomb1 (Epc1), a chromatin protein, can modulate skeletal muscle differentiation, although the mechanisms of this action have yet to be defined. Here we report that Epc1 recruits both serum response factor (SRF) and p300 to induce skeletal muscle differentiation. Epc1 interacted physically with SRF. Transfection of Epc1 to myoblast cells potentiated the SRF-induced expression of skeletal muscle-specific genes as well as multinucleation. Proximal CArG box in the skeletal alpha-actin promoter was responsible for the synergistic activation of the promoter-luciferase. Epc1 knockdown caused a decrease in the acetylation of histones associated with serum response element (SRE) of the skeletal alpha-actin promoter. The Epc1.SRF complex bound to the SRE, and the knockdown of Epc1 resulted in a decrease in SRF binding to the skeletal alpha-actin promoter. Epc1 recruited histone acetyltransferase activity, which was potentiated by cotransfection with p300 but abolished by si-p300. Epc1 directly bound to p300 in myoblast cells. Epc1+/- mice showed distortion of skeletal alpha-actin, and the isolated myoblasts from the mice had impaired muscle differentiation. These results suggest that Epc1 is required for skeletal muscle differentiation by recruiting both SRF and p300 to the SRE of muscle-specific gene promoters.
Journal of Biological Chemistry 05/2009; 284(24):16308-16. · 4.77 Impact Factor
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Hae Jin Kee,
Gwang Hyeon Eom, Hosouk Joung,
Sera Shin,
Ju-Ryoung Kim,
Young Kuk Cho,
Nakwon Choe,
Bo-Woong Sim,
Daewoong Jo,
Myung Ho Jeong,
Kyung Keun Kim,
Jeong-Sun Seo,
Hyun Kook
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ABSTRACT: Diverse cardiac diseases induce cardiac hypertrophy, which leads to dilatation and heart failure. We previously reported that hypertrophy can be blocked by class I histone deacetylase (HDAC) inhibitor, which prompted us to investigate the regulatory mechanism of class I HDACs. Cardiac hypertrophy was introduced by aortic banding, by infusion of isoproterenol or angiotensin II, or by swimming. Hypertrophic stimuli transiently elevated the activity of histone deacetylase-2 (Hdac2), a class I HDAC. In cardiomyocytes, forced expression of Hdac2 simulated hypertrophy in an Akt-dependent manner, whereas enzymatically inert Hdac2 H141A failed to do so. Hypertrophic stimuli induced the expression of heat shock protein (Hsp)70. The induced Hsp70 physically associated with and activated Hdac2. Hsp70 overexpression produced a hypertrophic phenotype, which was blocked either by siHdac2 or by a dominant negative Hsp70DeltaABD. In Hsp70.1(-/-) mice, cardiac hypertrophy and Hdac2 activation were significantly blunted. Heat shock either to cardiomyocytes or to mice activated Hdac2 and induced hypertrophy. However, heat shock-induced Hdac2 activation was blunted in the cardiomyocytes isolated from Hsp70.1(-/-) mice. These results suggest that the induction of Hsp70 in response to diverse hypertrophic stresses and the ensuing activation of HDAC2 trigger cardiac hypertrophy, emphasizing HSP70/HDAC2 as a novel mechanism regulating hypertrophy.
Circulation Research 11/2008; 103(11):1259-69. · 9.49 Impact Factor
