• Journal of Ginseng Research
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• v.47 no.1
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• pp.144-154
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• 2023

Background: As the major pathophysiological feature of obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) is vital for the occurrence of cardiovascular complications. The activation of calpain-1 mediates the production of endothelial reactive oxygen species (ROS) and impairs nitric oxide (NO) bioavailability, resulting in vascular endothelial dysfunction (VED). Ginsenoside Rg1 is thought to against endothelial cell dysfunction, but the potential mechanism of CIH-induced VED remains unclear. Methods: C57BL/6 mice and human coronary artery endothelial cells (HCAECs) were exposed to CIH following knockout or overexpression of calpain-1. The effect of ginsenoside Rg1 on VED, oxidative stress, mitochondrial dysfunction, and the expression levels of calpain-1, PP2A and p-eNOS were detected both in vivo and in vitro. Results: CIH promoted VED, oxidative stress and mitochondrial dysfunction accompanied by enhanced levels of calpain-1 and PP2A and reduced levels of p-eNOS in mice and cellular levels. Ginsenoside Rg1, calpain-1 knockout, OKA, NAC and TEMPOL treatment protected against CIH-induced VED, oxidative stress and mitochondrial dysfunction, which is likely concomitant with the downregulated protein expression of calpain-1 and PP2A and the upregulation of p-eNOS in mice and cellular levels. Calpain-1 overexpression increased the expression of PP2A, reduced the level of p-eNOS, and accelerated the occurrence and development of VED, oxidative stress and mitochondrial dysfunction in HCAECs exposed to CIH. Moreover, scavengers of O₂^·-, H₂O₂, complex I or mitoKATP abolished CIH-induced impairment in endothelial-dependent relaxation. Conclusion: Ginsenoside Rg1 may alleviate CIH-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.2
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• pp.177-182
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• 2014

This study was to determine the correlation between endothelial function and neuro-endocrine-immune (NEI) network through observing the changes of NEI network under the different endothelial dysfunction models. Three endothelial dysfunction models were established in male Wistar rats after exposure to homocysteine (Hcy), high fat diet (HFD) and Hcy+HFD. The results showed that there was endothelial dysfunction in all three models with varying degrees. However, the expression of NEI network was totally different. Interestingly, treatment with simvastatin was able to improve vascular endothelial function and restored the imbalance of the NEI network, observed in the Hcy+HFD group. The results indicated that NEI network may have a strong association with endothelial function, and this relationship can be used to distinguish different risk factors and evaluate drug effects.

• Biomedical Science Letters
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• v.12 no.3
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• pp.255-259
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• 2006

Reactive oxygen species (ROS) is one of the main pathological factors in endothelial disorder. For example, an atherosclerosis is induced by the dysfunction of vascular endothelial cells. The dysfunction of vascular endothelial cells cascades to secrete intercellular adhesion molecule (ICAM)-l substance by ROS. Therefore, The ROS is regraded as an important factor of the injury of vascular endothelial cells and inducement of atherosclerosis. Oxygen radical scavengers playa key role to prevention of many diseases mediated by oxidative stress of ROS. In this study, the toxic effect of ROS on vascular endothelial cells and the effect of antioxidant, vitamin E on bovine pulmonary vascular endothelial cell line (BPVEC) treated with hydrogen peroxide were examined by the colorimetric assay. ROS decreased remarkably cell viability according to the dose- and time-dependent manners. In protective effect of vitamin E on BPVEC treated with hydrogen peroxide, vitamin E increased remarkably cell viability compared with control after BPVEC were treated with $15{\mu}M$ hydrogen peroxide for 6 hours. From these results, it is suggested that ROS has cytotoxicity on cultured BPVEC and oxygen radical scavenger such as vitamin E is very effective in prevention of oxidative stress-induced cytotoxicity.

• Archives of Pharmacal Research
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• v.29 no.1
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• pp.1-15
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• 2006

Vascular endothelial cell injury or dysfunction has been implicated in the onset and' progression of cardiovascular diseases including atherosclerosis. A number of previous studies have demonstrated that the pro-oxidative and pro-inflammatory pathways within vascular endothelium play an important role in the initiation and progression of atherosclerosis, Recent evidence has provided compelling evidence to indicate that interleukin-4 (IL-4) can induce proc inflammatory environment via oxidative stress-mediated up-regulation of inflammatory mediators such as cytokine, chemokine, and adhesion molecules in vascular endothelial cells. In addition, apoptotic cell death within vascular endothelium has been hypothesized to be involved in the development of atherosclerosis. Emerging evidence has demonstrated that IL-4 can induce apoptosis of human vascular endothelial cells through the caspase-3-dependent pathway, suggesting that IL-4 can increase endothelial cell turnover by accelerated apoptosis, the event which may cause the dysfunction of the vascular endothelium. These studies will have a high probability of revealing new directions that lead to the development of clinical strategies toward the prevention and/or treatment for individuals with inflammatory vascular diseases including atherosclerosis.

• BMB Reports
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• v.52 no.2
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• pp.145-150
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• 2019

Endothelial dysfunction-induced lipid retention is an early feature of atherosclerotic lesion formation. Apoptosis of vascular smooth muscle cells (VSMCs) is one of the major modulating factors of atherogenesis, which accelerates atherosclerosis progression by causing plaque destabilization and rupture. However, the mechanism underlying VSMC apoptosis mediated by endothelial dysfunction in relation to atherosclerosis remains elusive. In this study, we reveal differential expression of several genes related to lipid retention and apoptosis, in conjunction with atherosclerosis, by utilizing a genetic mouse model of endothelial nitric oxide synthase (eNOS) deficiency manifesting endothelial dysfunction. Moreover, eNOS deficiency led to the enhanced susceptibility against pro-apoptotic insult in VSMCs. In particular, the expression of aggrecan, a major proteoglycan, was elevated in aortic tissue of eNOS deficient mice compared to wild type mice, and administration of aggrecan induced apoptosis in VSMCs. This suggests that eNOS deficiency may elevate aggrecan expression, which promotes apoptosis in VSMC, thereby contributing to atherosclerosis progression. These results may facilitate the development of novel approaches for improving the diagnosis or treatment of atherosclerosis.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.3
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• pp.201-209
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• 2014

The present study was designed to investigate the efficacy of selective $ET_A$ receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from $5^{th}$ to $8^{th}$ week of L-methionine treatment). On $52^{nd}$ day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective $ET_A$ receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.

• BMB Reports
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• v.47 no.1
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• pp.1-7
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• 2014

Atherosclerosis is a pathologic process occurring within the artery, in which many cell types, including T cell, macrophages, endothelial cells, and smooth muscle cells, interact, and cause chronic inflammation, in response to various inner- or outer-cellular stimuli. Atherosclerosis is characterized by a complex interaction of inflammation, lipid deposition, vascular smooth muscle cell proliferation, endothelial dysfunction, and extracellular matrix remodeling, which will result in the formation of an intimal plaque. Although the regulation and function of vascular smooth muscle cells are important in the progression of atherosclerosis, the roles of smooth muscle cells in regulating vascular inflammation are rarely focused upon, compared to those of endothelial cells or inflammatory cells. Therefore, in this review, we will discuss here how smooth muscle cells contribute or regulate the inflammatory reaction in the progression of atherosclerosis, especially in the context of the activation of various membrane receptors, and how they may regulate vascular inflammation.

• Clinical and Experimental Pediatrics
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• v.56 no.3
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• pp.130-134
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• 2013

Purpose: Anthracyclines have been utilized in the treatment of children with acute lymphoblastic leukemia (ALL). Recent studies have shown that anthracyclines may induce toxicity in the vascular endothelium. This study was performed using brachial artery reactivity (BAR) to evaluate vascular endothelial function in ALL patients who were treated with anthracycline chemotherapy. Methods: We included 21 children with ALL who received anthracycline chemotherapy and 20 healthy children. The cumulative dose of anthracyclines in the ALL patients was $142.5{\pm}18.2/m^2$. The last anthracycline dose was administered to the patients 2 to 85 months prior to their examination using BAR. The diameter of the brachial artery was measured in both groups using echocardiography, and BAR was calculated as the percentage change in the arterial diameter after release of the cuff relative to the baseline vessel diameter. Results: In the anthracycline-treated group, BAR was observed to be $3.4%{\pm}3.9%$, which was significantly lower than that observed in the control group ($12.1%{\pm}8.0%$, P<0.05). The time elapsed after the last anthracycline treatment and the age at the time of treatment did not affect the change in BAR (P =0.06 and P =0.13, respectively). Conclusion: These results provided evidence that treatment of ALL patients with anthracycline results in endothelial dysfunction. A larger cohort study and a longer follow-up period will be required to clarify the relationship between endothelial dysfunction resulting from anthracycline treatment for childhood ALL and occurrence of cardiovascular diseases later in life.

• International Journal of Oral Biology
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• v.33 no.4
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• pp.149-154
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• 2008

Porphyromonas gingivalis, a major periodontal pathogen, has been implicated in the initiation and progression of periodontal disease. Endothelial dysfunction (Editor note: Aberrant and dysfunction are somewhat redundant. The authors may want to choose one or the other.) contributes to chronic periodontal inflammation. Using cDNA-representational difference analysis, we found that P.gingivalis lipopolysaccharide differentially induces a number of genes in human microvascular endothelial cells. Among these upregulated genes, we focused on intercellular adhesion molecule-1 (VCAM-1), which is crucial for leukocyte recruitment during vascular inflammation. P. gingivalis LPS significantly increased the expression of vascular cell adhesion molecule-1 (VCAM-1) as well as ICAM-1. Promoter assays revealed that the transcription of these cell adhesion molecules was mainly regulated by nuclear factor-${\kappa}B$ (NF-${\kappa}B$) in endothelial cells. Furthermore, P. gingivalis LPS significantly increased leukocyte adhesiveness to microvascular endothelial cells and to aortic endothelium. Taken together, our results demonstrate that P. gingivalis LPS activates microvascular endothelial cells through NF-${\kappa}B$-dependent expression of cell adhesion molecules.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.1
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• pp.83-90
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• 2017

Advanced age is one of the risk factors for vascular diseases that are mainly caused by impaired nitric oxide (NO) production. It has been demonstrated that endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) and limits NO generation. Hence, arginase inhibition is suggested to be vasoprotective in aging. In this study, we examined the effects of intravenous injection of Piceatannol, an arginase inhibitor, on aged mice. Our results show that Piceatannol administration reduced the blood pressure in aged mice by inhibiting arginase activity, which was associated with NO production and reactive oxygen species generation. In addition, Piceatannol administration recovered $Ca^{2+}$/calmodulin-dependent protein kinase II phosphorylation, eNOS phosphorylation and eNOS dimer stability in the aged mice. The improved NO signaling was shown to be effective in attenuating the phenylephrine-dependent contractile response and in enhancing the acetylcholine-dependent vasorelaxation response in aortic rings from the aged mice. These data suggest Piceatannol as a potential treatment for vascular disease.