• The Korean Journal of Physiology and Pharmacology
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• v.27 no.3
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• pp.209-220
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• 2023

This study is to determine the regulation of nitric oxide synthase 3 (NOS3) by edaravone in mice with hypoxic pulmonary hypertension (HPH). C57BL/6J mice were reared in a hypoxic chamber. HPH mice were treated with edaravone or edaravone + L-NMMA (a NOS inhibitor). Lung tissue was collected for histological assessment, apoptosis analysis, and detection of malondialdehyde, superoxide dismutase, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and NOS3. The levels of serum TNF-α and IL-6 were also measured. Immunohistochemistry was used to visualize the expression of α-smooth muscle actin (SMA) in pulmonary arterioles. Edaravone treatment improved hemodynamics, inhibited right ventricular hypertrophy, increased NOS3 expression, and reduced pathological changes, pulmonary artery wall thickness, apoptotic pulmonary cells, oxidative stress, and the expression of TNF-α, IL-6, and α-SMA in HPH mice. L-NMMA treatment counteracted the lung protective effects of edaravone. In conclusion, edaravone might reduce lung damage in HPH mice by increasing the expression of NOS3.

• Journal of Ginseng Research
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• v.48 no.4
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• pp.405-416
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• 2024

Background: Hypoxic pulmonary hypertension (HPH) is the main pathological change in vascular remodeling, a complex cardiopulmonary disease caused by hypoxia. Some research results have shown that ginsenoside Rg1 (Rg1) can improve vascular remodeling, but the effect and mechanism of Rg1 on hypoxia-induced pulmonary hypertension are not clear. The purpose of this study was to discuss the potential mechanism of action of Rg1 on HPH. Methods: C57BL/6 mice, calpain-1 knockout mice and Pulmonary artery smooth muscle cells (PASMCs) were exposed to a low oxygen environment with or without different treatments. The effect of Rg1 and calpain-1 silencing on inflammation, fibrosis, proliferation and the protein expression levels of calpain-1, STAT3 and p-STAT3 were determined at the animal and cellular levels. Results: At the mouse and cellular levels, hypoxia promotes inflammation, fibrosis, and cell proliferation, and the expression of calpain-1 and p-STAT3 is also increased. Ginsenoside Rg1 administration and calpain-1 knockdown, MDL-28170, and HY-13818 treatment showed protective effects on hypoxia-induced inflammation, fibrosis, and cell proliferation, which may be associated with the downregulation of calpain-1 and p-STAT3 expression in mice and cells. In addition, overexpression of calpain 1 increased p-STAT3 expression, accelerating the onset of inflammation, fibrosis and cell proliferation in hypoxic PASMCs. Conclusion: Ginsenoside Rg1 may ameliorate hypoxia-induced pulmonary vascular remodeling by suppressing the calpain-1/STAT3 signaling pathway.

• Tuberculosis and Respiratory Diseases
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• v.46 no.6
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• pp.846-855
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• 1999

Background : Secondary pulmonary hypertension is an important final endpoint in patients with chronic hypoxic lung disease, accompanied by deterioration of pulmonary hemodynamics. The clinical diagnosis of pulmonary hypertension and/or cor pulmonale could be difficult, and simple noninvasive evaluation of pulmonary artery pressures has been an relevant clinical challenge for many years. Doppler echocardiography might to be a more reliable method for evaluating pulmonary hemodynamics in such patients in terms of the accuracy, reproducibility and easiness for obtaining an appropriate echocardiographic window than M-mode echocardiography. The aim of this study was to assess echocardiographic parameters associated with pulmonary arterial hypertension, defined by increasing right ventricular systolic pressure(RVSP), calculated from trans-tricuspid gradient in patients with chronic hypoxic lungs. Method : We examined 19 patients with chronic hypoxic lung disease, suspected pulmonary hypertension under the clinical guidelines by two dimensional echocardiography via the left parasternal and subcostal approach in a supine position. Doppler echocardiography measured RVSP from tricuspid regurgitant velocity in continuous wave with 2.5MHz transducer and acceleration time(AT) on right ventricular outflow tract in pulsed wave for the estimation of pulmonary arterial pressure. Results : On echocardiography, moderate to severe degree of pulmonary arterial hypertension was defined as RVSP more than 40mmHg, presenting tricuspid regurgitation. Increased right ventricular endsystolic diameter and shortened AT were noted in the increased RVSP group. Increased RVSP was correlated negatively with the shortening of AT. Other clinical data, including pulmonary functional parameters, arterial blood gas analysis and M mode echocardiographic parameters were not changed significantly with the increased RVSP. Conclusion : These findings suggest that shortened AT on pulsed doppler can be useful when quantifying pulmonary arterial pressure with increased RVSP in patients with chronic lung disease with hypoxemia. Doppler echocardiography in pulmonary hypertension of chronic hypoxic lungs is an useful option, based on noninvasiveness under routine clinical practice.

• Journal of Yeungnam Medical Science
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• v.25 no.1
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• pp.50-57
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• 2008

Pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein or pulmonary capillaries. Depending on the cause, pulmonary hypertension can be a severe disease with markedly decreased exercise tolerance and right-sided heart failure. Pulmonary hypertension can present as one of five different types: arterial, venous, hypoxic, thromboembolic, or miscellaneous. Chronic obstructive pulmonary disease with severe pulmonary hypertension is a rare disease. A 52-year-old man presented with a complaint of aggravating dyspnea. The mean pulmonary arterial pressure was 61.5 mmHg by Doppler echocardiogram. The patient was prescribed diuretics, digoxin, bronchodilator, sildenafil, bosentan and an oxygen supply. However, he ultimately died of cor pulmonale. Thus, diagnosis and early combination therapy are important.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.6
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• pp.641-647
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• 2016

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling of pulmonary arteries (PAs) and increased vascular resistance in the lung. Monocrotaline (MCT), a toxic alkaloid, is widely used for developing rat models of PAH caused by injury to pulmonary endothelial cells; however, characteristics of vascular functions in MCT-induced PAH vary and are not fully understood. Here, we investigated hypoxic pulmonary vasoconstriction (HPV) responses and effects of various vasoconstrictors with isolated/perfused lungs of MCT-induced PAH (PAH-MCT) rats. Using hematoxylin and eosin staining, we confirmed vascular remodeling (i.e., medial thickening of PA) and right ventricle hypertrophy in PAH-MCT rats. The basal pulmonary arterial pressure (PAP) and PAP increase by a raised flow rate (40 mL/min) were higher in the PAH-MCT than in the control rats. In addition, both high $K^+$ (40 mM KCl)- and angiotensin II-induced PAP increases were higher in the PAH-MCT than in the control rats. Surprisingly, application of a nitric oxide synthase inhibitor, L-$N^G$-Nitroarginine methyl ester (L-NAME), induced a marked PAP increase in the PAH-MCT rats, suggesting that endothelial functions were recovered in the three-week PAH-MCT rats. In addition, the medial thickening of the PA was similar to that in chronic hypoxia-induced PAH (PAH-CH) rats. However, the HPV response (i.e., PAP increased by acute hypoxia) was not affected in the MCT rats, whereas HPV disappeared in the PAH-CH rats. These results showed that vascular contractility and HPV remain robust in the MCT-induced PAH rat model with vascular remodeling.

• Clinical and Experimental Pediatrics
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• v.46 no.2
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• pp.167-172
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• 2003

Purpose : Pulmonary vascular hypertension is a common problem in congenital heart disease, the most common cardiac condition in childhood. However, the mechanisms responsible for this pathologic change, treatment, and prevention are poorly understood. Therefore, we studied the gene expression of vascular endothelial growth factor(VEGF) by using a hypoxic model of the pulmonary artery smooth muscle cells. Methods : The main pulmonary artery and its proximal branches of a 6 wk old Fischer rat were excised. They were cut into multiple small pieces and suspended in DMEM medium supplemented with 20% fetal bovine serum and incubated in 5% $CO_2$-95% air atmosphere. The smooth muscle cells were confirmed by immunostaining with smooth muscle myosin and ${\alpha}$-smooth muscle actin antibodies. The VEGF gene expression in the hypoxic group was compared with the one in control the group as well as the one in the starved group by RT-PCR and Northern blot hybridization. Results : There was no statistically significant difference among the control, hypoxic and starved groups. Conclusion : There are few studies of pulmonary vascular hypertension at the molecular level in Korea. Therefore, we studied the expression of VEGF gene in hypoxic pulmonary vascular smooth muscle cells. Further studies will be needed to find the difference between newly born and adult rats, or human and rat pulmonary vascular smooth muscle cells in gene expression. We hope that the study will lead to a better understanding of pulmonary vascular hypertension.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.3
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• pp.353-360
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• 2017

Several human diseases have been associated with mitochondrial voltage-dependent anion channel-1 (VDAC1) due to its role in calcium ion transportation and apoptosis. Recent studies suggest that VDAC1 may interact with endothelium-dependent nitric oxide synthase (eNOS). Decreased VDAC1 expression may limit the physical interaction between VDAC1 and eNOS and thus impair nitric oxide production, leading to cardiovascular diseases, including pulmonary arterial hypertension (PAH). In this report, we conducted meta-analysis of genome-wide expression data to identify VDAC1 influenced genes implicated in PAH pathobiology. First, we identified the genes differentially expressed between wild-type and Vdac1 knockout mouse embryonic fibroblasts in hypoxic conditions. These genes were deemed to be influenced by VDAC1 deficiency. Gene ontology analysis indicates that the VDAC1 influenced genes are significantly associated with PAH pathobiology. Second, a molecular signature derived from the VDAC1 influenced genes was developed. We suggest that, VDAC1 has a protective role in PAH and the gene expression signature of VDAC1 influenced genes can be used to i) predict severity of pulmonary hypertension secondary to pulmonary diseases, ii) differentiate idiopathic pulmonary artery hypertension (IPAH) patients from controls, and iii) differentiate IPAH from connective tissue disease associated PAH.