المؤلفون: Liyan Bai, Hae Jin Kee, Sin Young Choi, Young Mi Seok, Gwi Ran Kim, Seung-Jung Kee, Hyun Kook, Myung Ho Jeong

المصدر: Biomedicine & Pharmacotherapy, Vol 134, Iss , Pp 111162- (2021)

مصطلحات موضوعية: HDAC5, Hypertension, Vascular contraction, Vascular hypertrophy, Oxidative stress, Rho-associated protein kinase, Therapeutics. Pharmacology, RM1-950

الوصف: Non-specific histone deacetylase (HDAC) inhibition reduces high blood pressure in essential hypertensive animal models. However, the exact HDAC isoforms that play a critical role in controlling hypertension are not known. Here, we investigated the role of HDAC5 in vascular contraction, hypertrophy, and oxidative stress in the context of angiotensin II (Ang II)-induced hypertension.Genetic deletion of HDAC5 and treatment with class IIa HDAC inhibitors (TMP269 and TMP195) prevented Ang II-induced increases in blood pressure and arterial wall thickness. Hdac5-knockout mice were also resistant to the thromboxane A2 agonist (U46619)-induced vascular contractile response. Furthermore, the expression of Rho-associated protein kinase (ROCK) 2 was downregulated in the aortas of Ang II-treated Hdac5-knockout mice. Knockdown of HDAC5, RhoA, or ROCK2 reduced collagen gel contraction, whereas silencing of ROCK1 increased it. VSMC hypertrophy reduced on knocking down HDAC5, ROCK1, and ROCK2. Here we showed that genetic deletion of HDAC5 and pharmacological inhibition of class IIa HDACs ameliorated Ang II-induced ROS generation. Moreover, ROCK1 and ROCK2, the downstream targets of HDAC5, influenced ROS generation. The relative protein levels of HDAC5, ROCK1, and ROCK2 were increased both in the cytoplasm and nuclear fraction in response to Ang II stimulation in vascular smooth muscle cells. Inhibition of HDAC5 expression or activity reduced vascular hypertrophy, vasoconstriction, and oxidative stress in the Ang II-induced hypertension model. These findings indicate that HDAC5 may serve as a potential target in the treatment of hypertension.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S075333222031355XTest; https://doaj.org/toc/0753-3322Test

الوصول الحر: https://doaj.org/article/973a539d5f21462394fad1491c581e49Test

المؤلفون: Hae Jin Kee, Yuhee Ryu, Young Mi Seok, Sin Young Choi, Simei Sun, Gwi Ran Kim, Myung Ho Jeong

المصدر: Clinical Hypertension, Vol 25, Iss 1, Pp 1-13 (2019)

مصطلحات موضوعية: PCI34051, Hypertension, Arterial remodeling, Vascular relaxation, Inflammation, Medicine, Internal medicine, RC31-1245

الوصف: Abstract Background The dysregulation of histone deacetylase (HDAC) protein expression or its enzyme activity is implicated in a variety of diseases. Cardiac HDAC6 and HDAC8 enzyme activity induced by deoxycorticosterone acetate (DOCA) hypertension was attenuated by sodium valproate, a pan-HDAC inhibitor. However, the HDAC6-selective inhibitor, tubastatin A, did not attenuate angiotensin II-induced hypertension. The purpose of this study was to investigate whether PCI34051, an HDAC8-selective inhibitor, can modulate angiotensin II-induced hypertension and its regulatory mechanism. Methods An angiotensin II-regulated mouse model was used in this study. Animals received vehicle or PCI34051 (3 mg·kg − 1·day− 1) via intraperitoneal injection. Systolic blood pressure was measured by the tail-cuff method. Blood vessel thickness was measured following hematoxylin and eosin staining, VCAM-1 immunohistochemistry was performed in the aortas, and mRNA expression of renin-angiotensin system components, inflammation markers, and NADPH oxidase (Nox) was determined by RT-PCR. The effect of PCI34051 on vasorelaxation was studied in rat aortic rings, and its effect on nitric oxide (NO) production was determined using DAF-FM DA, a fluorescent dye, in human umbilical vascular endothelial cells (HUVECs). Results PCI34051 administration reduced systolic blood pressure via downregulation of angiotensin II receptor type 1 (AT1) mRNA expression. PCI34051 treatment attenuated vascular hypertrophy by decreasing E2F3 and GATA6 mRNA expression. Vascular relaxation after PCI34051 treatment was more dependent on vascular endothelial cells and it was blocked by an NO synthase (NOS) inhibitor. In addition, NO production increased in HUVECs after PCI34051 treatment; this was decreased by the NOS inhibitor. The expression of inflammatory molecules and adhesion molecules VCAM-1 and ICAM-1 decreased in the aortas of angiotensin II-infused mice after PCI34051 administration. However, PCI34051 did not affect Nox or its regulatory subunits. Conclusions PCI34051 lowered high blood pressure through modulation of arterial remodeling, vasoconstriction, and inflammation in an angiotensin II-induced hypertension model. We suggest that HDAC8 could be a potential therapeutic target for hypertension.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s40885-019-0118-8Test; https://doaj.org/toc/2056-5909Test

الوصول الحر: https://doaj.org/article/f5ea5ba24ecd42a0889082e4da43298fTest

المؤلفون: Gwi Ran Kim, Tingwei Zhao, Hae Jin Kee, Seung-Jung Kee, Myung Ho Jeong

المصدر: PLoS ONE, Vol 16, Iss 3, p e0249146 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Vascular remodeling and contraction contribute to the development of hypertension. We investigated the role of miR-212-5p and its downstream target in vascular smooth muscle cell (VSMC) proliferation, migration, and contraction. MicroRNA microarray and PCR analyses showed that miR-212-5p expression was increased with angiotensin II treatment in vivo and in vitro. Moreover, miR-212-5p mimic treatment attenuated and miR-212-5p inhibitor treatment increased VSMC proliferation and migration. Additionally, miR-212-5p mimic treatment suppressed VSMC contraction and related gene expression [Ras homolog gene family member A (RhoA) and Rho-associated protein kinase 2], while miR-212-5p inhibitor treatment exerted opposite effects. Bioinformatics analysis revealed that platelet-activating factor acetylhydrolase 1B2 (PAFAH1B2) is a target of miR-212-5p. miR-212-5p mimic treatment significantly reduced and miR-212-5p inhibitor treatment increased PAFAH1B2 expression. Furthermore, PAFAH1B2 expression was decreased in angiotensin II-treated aortic tissues and VSMCs. PAFAH1B2 was ubiquitously expressed in most adult rat tissues. In the vasculature, PAFAH1B2 was only distributed in the cytoplasm. PAFAH1B2 overexpression decreased A10 cell proliferation, while PAFAH1B2 knockdown increased A10 cell proliferation and cyclin D1 mRNA levels. PAFAH1B2 knockdown stimulated VSMC contraction and RhoA expression. These results suggest that miR-212-5p and PAFAH1B2 are novel negative regulators of VSMC proliferation, migration, and contraction in hypertension.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/90475609af534d77ae231b9417edefd3Test

المؤلفون: Yuhee Ryu, Hae Jin Kee, Simei Sun, Young Mi Seok, Sin Young Choi, Gwi Ran Kim, Seung-Jung Kee, Marc Pflieger, Thomas Kurz, Hyung-Seok Kim, Myung Ho Jeong

المصدر: PLoS ONE, Vol 14, Iss 3, p e0213186 (2019)

مصطلحات موضوعية: Medicine, Science

الوصف: OBJECTIVE:Non-selective histone deacetylase (HDAC) inhibitors are known to improve hypertension. Here, we investigated the therapeutic effect and regulatory mechanism of the class I HDAC selective inhibitors, MS-275 and RGFP966, in angiotensin (Ang) II-induced hypertensive mice. METHODS AND RESULTS:MS-275 inhibited the activity of HDAC1, HDAC2, and HDAC3, while RGFP966 weakly inhibited that of HDAC3 in a cell-free system. MS-275 and RGFP966 treatment reduced systolic blood pressure and thickness of the aorta wall in Ang II-induced hypertensive mice. MS-275 treatment reduced aorta collagen deposition, as determined by Masson's trichrome staining. MS-275 decreased the components of the renin angiotensin system and increased vascular relaxation of rat aortic rings via the nitric oxide (NO) pathway. NO levels reduced by Ang II were restored by MS-275 treatment in vascular smooth muscle cells (VSMCs). However, MS-275 dose (3 mg·kg-1·day-1) was not enough to induce NO production in vivo. In addition, MS-275 did not prevent endothelial nitric oxide synthase (eNOS) uncoupling in the aorta of Ang II-induced mice. Treatment with MS-275 failed to inhibit Ang II-induced expression of NADPH oxidase (Nox)1, Nox2, and p47phox. MS-275 treatment reduced proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1, as well as adhesion molecules. Histological analysis showed that Ang II-induced macrophage infiltration was reduced by MS-275 and RGFP966 administration. CONCLUSIONS:Our results indicate that class I HDAC selective inhibitors may be good therapeutic agents for the treatment of hypertension through the regulation of vascular remodeling and vasoconstriction, as well as inflammation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/5d90e416dfc8460cb50d29d0a0f2467aTest

المؤلفون: Sin Young Choi, Zhe Hao Piao, Li Jin, Jung Ha Kim, Gwi Ran Kim, Yuhee Ryu, Ming Quan Lin, Hyung-Seok Kim, Hae Jin Kee, Myung Ho Jeong

المصدر: PLoS ONE, Vol 11, Iss 11, p e0167340 (2016)

مصطلحات موضوعية: Medicine, Science

الوصف: Piceatannol, a resveratrol metabolite, is a phenolic compound found in red wine and grapes. We investigated the effect of piceatannol on renal fibrosis and histone deacetylase (HDAC) expression in a mouse model of unilateral ureteral obstruction (UUO). Fibrosis was established by UUO and piceatannol was intraperitoneally injected for 2 weeks. Piceatannol suppressed extracellular matrix (ECM) protein deposition including collagen type I and fibronectin as well as connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) in UUO kidneys. However, the expressions of epithelial-mesenchymal transition (EMT) marker genes, such as N-cadherin and E-cadherin, were not changed in the kidneys after UUO. Masson's trichrome staining and fluorescence immunostaining showed that piceatannol administration attenuated collagen deposition in UUO kidneys. HDAC1, HDAC4, HDAC5, HDAC6, and HDAC10 protein expression was upregulated in UUO kidneys, whereas that of HDAC8 was downregulated. Piceatannol treatment significantly reduced HDAC4 and HDAC5 protein expression. Further, piceatannol attenuated phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) in UUO kidneys, but not that of transforming growth factor beta1-Smad2/3. These results suggest that class I HDACs and class IIa/b HDACs are involved in renal fibrosis development. Piceatannol may be a beneficial therapeutic agent for treating renal fibrosis via reduction of HDAC4 and HDAC5 protein expression or suppression of the p38-MAPK signaling pathway.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC5130266?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/e9bc484dc39547d0aae1efe959ad3deaTest

المؤلفون: Gwi Ran Kim (3370784), Tingwei Zhao (10432865), Hae Jin Kee (824000), Seung-Jung Kee (824001), Myung Ho Jeong (8201055)

مصطلحات موضوعية: Biochemistry, Cell Biology, Genetics, Molecular Biology, Physiology, Pharmacology, Biotechnology, Developmental Biology, Marine Biology, Cancer, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, miR -212-5p inhibitor treatment, 10 cell proliferation, PAFAH 1B knockdown, cyclin D 1 mRNA levels, PCR, PAFAH 1B expression, miR -212-5p expression, Ras homolog gene family member, PAFAH 1B overexpression, platelet-activating factor acetylhy., VSMC proliferation, adult rat tissues, miR -212-5p, angiotensin II treatment, target PAFAH 1B, VSMC contraction, miR -212-5p miR -212-5p, angiotensin II-treated aortic tissues

الوصف: (PDF)

العلاقة: https://figshare.com/articles/journal_contribution/S1_File_-/14301563Test

الإتاحة: https://doi.org/10.1371/journal.pone.0249146.s001Test

المؤلفون: Seung-Jung Kee, Marc Pflieger, Thomas Kurz, Hae Jin Kee, Gwi Ran Kim, Simei Sun, Matthias U. Kassack, Sin Young Choi, Young Mi Seok, Yuhee Ryu, Myung Ho Jeong

المصدر: Journal of Cellular and Molecular Medicine

مصطلحات موضوعية: 0301 basic medicine, Male, Angiotensin receptor, medicine.medical_specialty, Vascular smooth muscle, hypertension, medicine.drug_class, Aortic Diseases, Muscle, Smooth, Vascular, Nitric oxide, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, calcium calmodulin‐dependent protein kinase II, Internal medicine, Rats, Inbred SHR, Renin–angiotensin system, medicine, Animals, Antihypertensive Agents, Histone deacetylase 5, vascular hyperplasia, Angiotensin II, Histone deacetylase inhibitor, Cell Biology, Original Articles, HDAC5, HDAC4, Rats, Histone Deacetylase Inhibitors, 030104 developmental biology, Endocrinology, chemistry, Gene Expression Regulation, Vasoconstriction, 030220 oncology & carcinogenesis, Benzamides, Molecular Medicine, Original Article, medicine.symptom

الوصف: Here, we report that LMK235, a class I and histone deacetylase (HDAC6)‐preferential HDAC inhibitor, reduces hypertension via inhibition of vascular contraction and vessel hypertrophy. Angiotensin II‐infusion mice and spontaneously hypertensive rats (SHRs) were used to test the anti‐hypertensive effect of LMK235. Daily injection of LMK235 lowered angiotensin II‐induced systolic blood pressure (BP). A reduction in systolic BP in SHRs was observed on the second day when SHRs were treated with 3 mg/kg LMK235 every 3 days. However, LMK235 treatment did not affect angiotensin‐converting enzyme 1 and angiotensin II receptor mRNA expression in either hypertensive model. LMK235, acting via the nitric oxide pathway, facilitated the relaxing of vascular contractions induced by a thromboxane A2 agonist in the rat aortic and mesenteric artery ring test. In addition, LMK235 increased nitric oxide production in HUVECs and inhibited the increasing of aortic wall thickness in both animal hypertensive models. LMK235 decreased the enhanced cell cycle‐related genes cyclin D1 and E2F3 in angiotensin II‐infusion mice and restored the decreased p21 expression. In addition, LMK235 suppressed calcium calmodulin‐dependent protein kinase II (CaMKII) α, which is related to vascular smooth muscle cell proliferation. Inhibition or knockdown of HDAC5 blocked the CaMKIIα‐induced cell cycle gene expression. Immunoprecipitation demonstrated that class I HDACs were involved in the inhibition of CaMKII α‐induced HDAC4/5 by LMK235. We suggest that LMK235 should be further investigated for its use in the development of new therapeutic options to treat hypertension via reducing vascular hyperplasia or vasoconstriction.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::864b3a40fdb5d328dc25c76d3bf1cb31Test
http://europepmc.org/articles/PMC6433685Test

المؤلفون: Myung Ho Jeong, Gwi Ran Kim, Hae Jin Kee, Li Jin, Yuhee Ryu, Simei Sun, Sin Young Choi

المصدر: Journal of Cellular and Molecular Medicine

مصطلحات موضوعية: Male, 0301 basic medicine, Cardiac fibrosis, Gentisates, cardiac fibrosis, Constriction, Pathologic, 030204 cardiovascular system & hematology, Pharmacology, Electrocardiography, Mice, chemistry.chemical_compound, 0302 clinical medicine, gentisic acid, Fibrosis, Diltiazem, Phosphorylation, Gentisic acid, Aorta, cardiac hypertrophy, Brain natriuretic peptide, GATA4/Sp1, Bisoprolol, cardiovascular system, Molecular Medicine, Original Article, Hypertrophy, Left Ventricular, medicine.drug, MAP Kinase Signaling System, Sp1 Transcription Factor, medicine.drug_class, Cardiomegaly, 03 medical and health sciences, transverse aortic constriction, Pressure, medicine, Animals, Beta blocker, Pressure overload, ERK1/2 MAPK signalling pathway, business.industry, Myocardium, Original Articles, Cell Biology, medicine.disease, GATA4 Transcription Factor, 030104 developmental biology, Gene Expression Regulation, chemistry, business

الوصف: We previously reported that gentisic acid (2,5‐dihydroxybenzoic acid) is the third most abundant phenolic component of Dendropanax morbifera branch extracts. Here, we investigated its effects on cardiac hypertrophy and fibrosis in a mouse model of pressure overload and compared them to those of the beta blocker bisoprolol and calcium channel blocker diltiazem. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC). Beginning 2 weeks after this procedure, the mice were given daily intraperitoneal injections of gentisic acid (100 mg/kg/d), bisoprolol (5 mg/kg/d) or diltiazem (10 mg/kg/d) for 3 weeks. Cardiac hypertrophy was evaluated by the heart weight‐to‐body weight ratio, the cardiomyocyte cross‐sectional area after haematoxylin and eosin staining, and echocardiography. Markers of cardiac hypertrophy and fibrosis were tested by reverse transcription‐quantitative real‐time polymerase chain reaction, western blotting and Masson's trichrome staining. The suppressive effects of gentisic acid treatment on TAC‐induced cardiac hypertrophy and fibrosis were comparable to those of bisoprolol administration. Cardiac hypertrophy was reversed and left ventricular septum and posterior wall thickness were restored by gentisic acid, bisoprolol and diltiazem treatment. Cardiac hypertrophic marker gene expression and atrial and brain natriuretic peptide levels were decreased by gentisic acid and bisoprolol, as were cardiac (interstitial and perivascular) fibrosis and fibrosis‐related gene expression. Cardiac hypertrophy‐associated upregulation of the transcription factors GATA4 and Sp1 and activation of extracellular signal‐regulated kinase 1/2 were also negated by these drugs. These results suggest that gentisic acid could serve as a therapeutic agent for cardiac hypertrophy and fibrosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1f18040d5769ef9bb2fa8b1a356471c6Test
https://doi.org/10.1111/jcmm.13869Test

المؤلفون: Gwi Ran Kim (3370784), Tingwei Zhao (10432865), Hae Jin Kee (824000), Seung-Jung Kee (824001), Myung Ho Jeong (8201055)

مصطلحات موضوعية: Biochemistry, Cell Biology, Genetics, Molecular Biology, Physiology, Pharmacology, Biotechnology, Developmental Biology, Marine Biology, Cancer, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, miR -212-5p inhibitor treatment, 10 cell proliferation, PAFAH 1B knockdown, cyclin D 1 mRNA levels, PCR, PAFAH 1B expression, miR -212-5p expression, Ras homolog gene family member, PAFAH 1B overexpression, platelet-activating factor acetylhy., VSMC proliferation, adult rat tissues, miR -212-5p, angiotensin II treatment, target PAFAH 1B, VSMC contraction, miR -212-5p miR -212-5p, angiotensin II-treated aortic tissues

الوصف: (A ) Systolic blood pressure was measured in vehicle- and angiotensin II-treated mice (n = 12 per group). (B) Representative images of H&E staining of aortic tissues (n = 6 per group). Scale bar = 100 μm. ( C ) Quantified aortic wall thickness (n = 6 per group) in vehicle- and angiotensin II-treated mice. ( D ) Aortic miR-212-5plevels were evaluated using RT-PCR. *** P < 0.001 versus the vehicle-treated group. ( E ) VSMCs were serum-starved and then treated with angiotensin II (1 μM) for 1 day. miR-212-5p levels were evaluated by RT-PCR. ** P < 0.01 versus the vehicle-treated group. ( F,G ) Aortic miR-212-3p and miR-6937-5p levels were evaluated using RT-PCR. NS indicates not significant.

العلاقة: https://figshare.com/articles/figure/miR_212-5p_expression_is_increased_in_aortic_tissues_from_angiotensin_II-treated_mice_and_VSMCs_/14301566Test

الإتاحة: https://doi.org/10.1371/journal.pone.0249146.g001Test

المؤلفون: Gwi Ran Kim (3370784), Tingwei Zhao (10432865), Hae Jin Kee (824000), Seung-Jung Kee (824001), Myung Ho Jeong (8201055)

مصطلحات موضوعية: Biochemistry, Cell Biology, Genetics, Molecular Biology, Physiology, Pharmacology, Biotechnology, Developmental Biology, Marine Biology, Cancer, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, miR -212-5p inhibitor treatment, 10 cell proliferation, PAFAH 1B knockdown, cyclin D 1 mRNA levels, PCR, PAFAH 1B expression, miR -212-5p expression, Ras homolog gene family member, PAFAH 1B overexpression, platelet-activating factor acetylhy., VSMC proliferation, adult rat tissues, miR -212-5p, angiotensin II treatment, target PAFAH 1B, VSMC contraction, miR -212-5p miR -212-5p, angiotensin II-treated aortic tissues

الوصف: (A) VSMCs were transfected with control or miR-212-5p mimic for 2 days. Cell proliferation was determined by the MTT assay. ** P < 0.01 versus the control mimic group. ( B) Direct cell counting showing in vitro proliferation of VSMCs transfected with miR-212-5p mimic. ** P < 0.01 versus the control mimic group. ( C ) After transfection of VSMCs with miR-212-5p mimic, cyclin D1 transcript levels were determined by RT-PCR. * P < 0.05 versus the control mimic group. ( D,E ) VSMCs transfected with miR-212-5p mimic were incubated with BrdU and then immunostained with an anti-BrdU antibody. Scale bar = 100 μm. The number of BrdU-positive cells was quantified. ** P < 0.01 versus the control mimic group. ( F,G ) VSMCs were transfected with control or miR-212-5p mimic, and cell migration was assessed for 15~24 h by the scratch-wound assay. ** P < 0.01 versus the control mimic group.

العلاقة: https://figshare.com/articles/figure/miR-212-5p_overexpression_attenuates_VSMC_proliferation_and_migration_/14301569Test

الإتاحة: https://doi.org/10.1371/journal.pone.0249146.g002Test