• Genomics & Informatics
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• v.10 no.4
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• pp.244-248
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• 2012

Oxidative stress, which results in an excessive product of reactive oxygen species (ROS), is one of the fundamental mechanisms of the development of hypertension. In the vascular system, ROS have physical and pathophysiological roles in vascular remodeling and endothelial dysfunction. In this study, ROS-hypertension-related genes were collected by the biological literature-mining tools, such as SciMiner and gene2pubmed, in order to identify the genes that would cause hypertension through ROS. Further, single nucleotide polymorphisms (SNPs) located within these gene regions were examined statistically for their association with hypertension in 6,419 Korean individuals, and pathway enrichment analysis using the associated genes was performed. The 2,945 SNPs of 237 ROS-hypertension genes were analyzed, and 68 genes were significantly associated with hypertension (p < 0.05). The most significant SNP was rs2889611 within MAPK8 (p = $2.70{\times}10^{-5}$; odds ratio, 0.82; confidence interval, 0.75 to 0.90). This study demonstrates that a text mining approach combined with association analysis may be useful to identify the candidate genes that cause hypertension through ROS or oxidative stress.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.42
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• pp.23.1-23.11
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• 2020

Background: 4-Hexylresorcinol (4HR) is able to increase angiogenesis. However, its molecular mechanism in the human endothelial cells has not been clarified. Methods: As endothelial cells are important in angiogenesis, we treated the human umbilical vein endothelial cells (HUVECs) with 4HR and investigated protein expressional changes by immunoprecipitation high-performance liquid chromatography (IP-HPLC) using 96 antisera. Results: Here, we found that 4HR upregulated transforming growth factor-β (TGF-β)/SMAD/vascular endothelial growth factor (VEGF) signaling, RAF-B/ERK and p38 signaling, and M2 macrophage polarization pathways. 4HR also increased expression of caspases and subsequent cellular apoptosis. Mechanistically, 4HR increased TGF-β1 production and subsequent activation of SMADs/VEGFs, RAF-B/ERK and p38 signaling, and M2 macrophage polarization. Conclusion: Collectively, 4HR activates TGF-β/SMAD/VEGF signaling in endothelial cells and induced vascular regeneration and remodeling for wound healing.

• Molecules and Cells
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• v.38 no.6
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• pp.528-534
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• 2015

Hypoxia-inducible factor (HIF) is a key regulator of tumor growth and angiogenesis. Recent studies have shown that, BIX01294, a G9a histone methyltransferase (HMT)-specific inhibitor, induces apoptosis and inhibits the proliferation, migration, and invasion of cancer cells. However, not many studies have investigated whether inhibition of G9a HMT can modulate HIF-$1{\alpha}$ stability and angiogenesis. Here, we show that BIX01294 dose-dependently decreases levels of HIF-$1{\alpha}$ in HepG2 human hepatocellular carcinoma cells. The half-life of HIF-$1{\alpha}$, expression of proline hydroxylase 2 (PHD2), hydroxylated HIF-$1{\alpha}$ and von Hippel-Lindau protein (pVHL) under hypoxic conditions were decreased by BIX01294. The mRNA expression and secretion of vascular endothelial growth factor (VEGF) were also significantly reduced by BIX01294 under hypoxic conditions in HepG2 cells. BIX01294 remarkably decreased angiogenic activity induced by VEGF in vitro, ex vivo, and in vivo, as demonstrated by assays using human umbilical vein endothelial cells (HUVECs), mouse aortic rings, and chick chorioallantoic membranes (CAMs), respectively. Furthermore, BIX01294 suppressed VEGF-induced matrix metalloproteinase 2 (MMP2) activity and inhibited VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), focal adhesion kinase (FAK), and paxillin in HUVECs. In addition, BIX01294 inhibited VEGF-induced formation of actin cytoskeletal stress fibers. In conclusion, we demonstrated that BIX01294 inhibits HIF-$1{\alpha}$ stability and VEGF-induced angiogenesis through the VEGFR-2 signaling pathway and actin cytoskeletal remodeling, indicating a promising approach for developing novel therapeutics to stop tumor progression.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.6
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• pp.499-506
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• 2015

Angiotensin II (Ang II), a key mediator of hypertensive, causes structural changes in the arteries (vascular remodeling), which involve alterations in cell growth, vascular smooth muscle cell (VSMC) hypertrophy. Ang II promotes fibrotic factor like IGFBP5, which mediates the profibrotic effects of Ang II in the heart and kidneys, lung and so on. The purpose of this study was to identify the signaling pathway of IGFBP5 on cell proliferation and migration of Ang II-stimulated VSMC. We have been interested in Ang II-induced IGFBP5 and were curious to determine whether a Pitavastatin would ameliorate the effects. Herein, we investigated the question of whether Ang II induced the levels of IGFBP5 protein followed by proliferation and migration in VSMC. Pretreatment with the specific Angiotensin receptor type 1 (AT1) inhibitor (Losartan), Angiotensin receptor type 2 (AT2) inhibitor (PD123319), MAPK inhibitor (U0126), ERK1/2 inhibitor (PD98059), P38 inhibitor (SB600125) and PI3K inhibitor (LY294002) resulted in significantly inhibited IGFBP5 production, proliferation, and migration in Ang II-stimulated VSMC. In addition, IGFBP5 knockdown resulted in modulation of Ang II induced proliferation and migration via IGFBP5 induction. In addition, Pitavastatin modulated Ang II induced proliferation and migration in VSMC. Taken together, our results indicated that Ang II induces IGFBP5 through AT1, ERK1/2, P38, and PI3K signaling pathways, which were inhibited by Pitavastatin. These findings may suggest that Pitavastatin has an effect on vascular disease including hypertension.

• Archives of Reconstructive Microsurgery
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• v.13 no.2
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• pp.101-106
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• 2004

Purpose : This study evaluated the effect of VEGF in the arterial anastomosis by using light and electron microscopy. Marerials and method : Rats underwent femoral arterial end-to-end anastomosis after transection and topical VEGF treatment. The proximal and distal segments of the femoral arteries was drenched with 1 drop of VEGF $(100ng/100{\mu}l/bottle)$. and when half of the repair was finished, the other 1 drop was drenched and then the repair was continued to complete the anastomosis. Gross and histologic characteristics of arterial wall were assessed after 3 days, 1, 3 and 5 weeks. In the control group, normal saline solution instead of VEGF was dropped with the same method in the anastomosis. Results : The histologic findings of the arterial wall were the vascular remodeling with the infiltration of inflammatory cells at early stages and the tissue fibrosis at lately stages in the anastomotic sites of the control and the VEGF-treated groups. The scanning electron microscopic results were; (1) the anastomotic sites were covered by many irregular cells with long cytoplasmic processes at the early stages. (2) After 1 week, endothelial cells started to cover the anastomotic sites. (3) After 3 weeks, the anastomotic sites were partially covered by endothelial cells in the control group. (4) After 5 weeks, the anastomotic sites were completely covered by endothelial cells in the control and VEGF-treated groups. (5) In the VEGF-treated group, the anastomotic site was completely covered by endothelial cells which directed parallel to longitudinal axis of arteries after 3 weeks. Conclusion : Topical VEGF maintained luminal integrity by decreasing fibrosis and increasing re-endothelialization. These findings suggest that topical VEGF may be a promising new strategy to enhance healing and improve the outcome of vascular anastomosis.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.1
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• pp.1-8
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• 2013

Understanding the cellular and molecular mechanisms involved in the development and progression of pulmonary hypertension (PH) remains imperative if we are to successfully improve the quality of life and life span of patients with the disease. A whole plethora of mechanisms are associated with the development and progression of PH. Such complexity makes it difficult to isolate one particular pathway to target clinically. Changes in intracellular free calcium concentration, the most common intracellular second messenger, can have significant impact in defining the pathogenic mechanisms leading to its development and persistence. Signaling pathways leading to the elevation of $[Ca^{2+}]_{cyt}$ contribute to pulmonary vasoconstriction, excessive proliferation of smooth muscle cells and ultimately pulmonary vascular remodeling. This current review serves to summarize the some of the most recent advances in the regulation of calcium during pulmonary hypertension.

• Journal of Life Science
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• v.18 no.6
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• pp.891-896
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• 2008

The function of mast cells as effector cells in allergy has been extensively studied. Mast cells activated through high affinity IgE-receptor ($Fc{\varepsilon}RI$) release diverse mediators, and lead to smooth muscle constriction, vasodilation, increase of vascular permeability, leukocyte recruitment and activation, mucus secretion, and tissue proliferation and remodeling. However, various other immunological and non-immunological signals can lead to the activation of mast cells. In resent years, mast cells have been identified to be involved in a complex range of immune functions. Mast cells can be important as key players in the regulation of innate as well as adapted immune responses, and may influence the development of allergy, autoimmune disorder and peripheral tolerance. This review summarizes the recent advances in the understanding of effector functions of mast cells in immune responses.

• Clinical and Experimental Pediatrics
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• v.59 no.6
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• pp.262-270
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• 2016

Purpose: Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. Methods: The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. Results: The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-${\alpha}$, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. Conclusion: Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function.

• Clinical and Experimental Pediatrics
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• v.53 no.1
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• pp.41-47
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• 2010

Purpose : Adiponectin is an endogenous modulator of vascular remodeling that suppresses vascular inflammation. However, the role of adiponectin in Kawasaki disease (KD) has not been elucidated. The purpose of this study is to investigate the correlation between serum adiponectin level and several parameters, such as interleukin (IL)-6, tumor necrosis factor $(TNF)-{\alpha}$, lipid profile, and C reactive protein (CRP), and to clarify the association between adiponectin and cardiac function. Methods : Twenty-two KD patients (22 patients in acute phase and 20 patients in subacute phase) were enrolled in the study group. The control group consisted of 31 subjects (13 febrile patients and 18 healthy children). Both groups underwent blood sampling and tissue Doppler imaging (TDI). Results : CRP was significantly increased in the KD group compared with the control group. There were no significant differences in serum $TNF-{\alpha}$, IL-6, and adiponectin levels between groups. However, a negative correlation was found between adiponectin level and CRP level or platelet count. Systolic myocardial velocity and A myocardial velocity measured by TDI were decreased significantly in the acute KD group compared with the subacute KD group and control group. Positive correlations were found between adiponectin level and systolic myocardial velocity or A myocardial velocity. Conclusion : In acute KD patients, low adiponectin level was related to severe inflammatory reactions and decreased left ventricular functions.

• Imaging Science in Dentistry
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• v.50 no.3
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• pp.199-208
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• 2020

Purpose: This study was performed to introduce an in vivo hybrid multimodality technique involving the coregistration of micro-computed tomography (micro-CT) and high-resolution magnetic resonance imaging (HR-MRI) to concomitantly visualize and quantify mineralization and vascularization at follow-up in a rat model. Materials and Methods: Three adult female rats were randomly assigned as test subjects, with 1 rat serving as a control subject. For 20 weeks, the test rats received a weekly intravenous injection of 30 ㎍/kg zoledronic acid, and the control rat was administered a similar dose of normal saline. Bilateral extraction of the lower first and second molars was performed after 10 weeks. All rats were scanned once every 4 weeks with both micro-CT and HR-MRI. Micro-CT and HR-MRI images were registered and fused in the same 3-dimensional region to quantify blood flow velocity and trabecular bone thickness at T0 (baseline), T4 (4 weeks), T8 (8 weeks), T12 (12 weeks), T16 (16 weeks), and T20 (20 weeks). Histological assessment was the gold standard with which the findings were compared. Results: The histomorphometric images at T20 aligned with the HR-MRI findings, with both test and control rats demonstrating reduced trabecular bone vasculature and blood vessel density. The micro-CT findings were also consistent with the histomorphometric changes, which revealed that the test rats had thicker trabecular bone and smaller marrow spaces than the control rat. Conclusion: The combination of micro-CT and HR-MRI may be considered a powerful non-invasive novel technique for the longitudinal quantification of localized mineralization and vascularization.