• The Korean Journal of Physiology and Pharmacology
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• 제21권3호
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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.

• Clinical and Experimental Pediatrics
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• 제61권9호
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• pp.271-278
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• 2018

Purpose: Abnormal potassium channels expression affects vessel function, including vascular tone and proliferation rate. Diverse potassium channels, including voltage-gated potassium (Kv) channels, are involved in pathological changes of pulmonary arterial hypertension (PAH). Since the role of the Kv1.7 channel in PAH has not been previously studied, we investigated whether Kv1.7 channel expression changes in the lung tissue of a monocrotaline (MCT)-induced PAH rat model and whether this change is influenced by the endothelin (ET)-1 and reactive oxygen species (ROS) pathways. Methods: Rats were separated into 2 groups: the control (C) group and the MCT (M) group (60 mg/kg MCT). A hemodynamic study was performed by catheterization into the external jugular vein to estimate the right ventricular pressure (RVP), and pathological changes in the lung tissue were investigated. Changes in protein and mRNA levels were confirmed by western blot and polymerase chain reaction analysis, respectively. Results: MCT caused increased RVP, medial wall thickening of the pulmonary arterioles, and increased expression level of ET-1, ET receptor A, and NADPH oxidase (NOX) 4 proteins. Decreased Kv1.7 channel expression was detected in the lung tissue. Inward-rectifier channel 6.1 expression in the lung tissue also increased. We confirmed that ET-1 increased NOX4 level and decreased glutathione peroxidase-1 level in pulmonary artery smooth muscle cells (PASMCs). ET-1 increased ROS level in PASMCs. Conclusion: Decreased Kv1.7 channel expression might be caused by the ET-1 and ROS pathways and contributes to MCT-induced PAH.

• Clinical and Experimental Pediatrics
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• 제53권1호
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• pp.93-96
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• 2010

15년전 심방중격 결손증 진단을 받은 47세 남자 환자가 심도자 검사를 위해 입원하였다. 환자는 입술과 손톱에서 명확한 청색증을 보이고 있었으며 심한 폐동맥 고혈압을 나타내고 있었다. 본 환자는 지난 수년간 아이젠멩거 증후군으로 진단되어 대증적 치료만을 받아오고 있었다. 심도자 검사 후 환자는 흡입형 Iloprost 치료를 시작 하였으며 성공적으로 심방중격결손증 수술을 받을 수 있었다. 환자는 수술 후에도 치료를 지속하였다.

• Korean Circulation Journal
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• 제53권5호
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• pp.313-327
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• 2023

Background and Objectives: Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Recent advances in PAH-specific drugs have improved its outcomes, although the healthcare burden of novel therapeutics may lead to a discrepancy in outcomes between developing and developed countries. We analyzed how the epidemiology and clinical features of PAH has changed through the rapidly advancing healthcare infrastructure in South Korea. Methods: PAH was defined according to a newly devised 3-component algorithm. Using a nationwide health insurance claims database, we delineated annual trends in the prevalence, incidence, medication prescription pattern, and 5-year survival of PAH in Korea. Cumulative survival and potential predictors of mortality were also assessed among 2,151 incident PAH cases. Results: Between 2002 or 2004 and 2018, the prevalence and incidence of PAH increased 75-fold (0.4 to 29.9 per million people) and 12-fold (0.5 to 6.3 per million person-years), respectively. The proportion of patients on combination PAH-specific drug therapy has also steadily increased up to 29.0% in 2018. Among 2,151 incident PAH cases (median [interquartile range] age, 50 [37-62] years; 67.2% female), the 5-year survival rate and median survival duration were 71.8% and 13.1 years, respectively. Independent predictors of mortality were age, sex, etiology of PAH, diabetes, dyslipidemia, and chronic kidney disease. Conclusions: This nationwide study delineated that the prevalence and incidence of PAH have grown rapidly in Korea since the early 2000s. The use of combination therapy has also increased, and the 5-year survival rate of PAH in Korea was similar to those in western countries.

• Clinical and Experimental Pediatrics
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• 제55권8호
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• pp.297-300
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• 2012

Symptomatic pulmonary arterial hypertension (PAH) in patients with isolated atrial septal defect (ASD) is rare during infancy. We report a case of isolated ASD with severe PAH in an infant who developed airway obstruction as cardiomegaly progressed. The patient presented with recurrent severe respiratory insufficiency and failure to thrive before the repair of the ASD. Echocardiography confirmed volume overload on the right side of heart and severe PAH (tricuspid regurgitation [TR] with a peak pressure gradient of 55 to 60 mmHg). The chest radiographs demonstrated severe collapse of both lung fields, and a computed tomography scan showed narrowing of the main bronchus because of an intrinsic cause, as well as a dilated pulmonary artery compressing the main bronchus on the left and the intermediate bronchus on the right. ASD patch closure was performed when the infant was 8 months old. After the repair of the ASD, echocardiography showed improvement of PAH (TR with a peak pressure gradient of 22 to 26 mmHg), and the patient has not developed recurrent respiratory infections while showing successful catch-up growth. In infants with symptomatic isolated ASD, especially in those with respiratory insufficiency associated with severe PAH, extrinsic airway compression should be considered. Correcting any congenital heart diseases in these patients may improve their symptoms.

• BMB Reports
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• 제55권11호
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• pp.565-570
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• 2022

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease whose pathogenesis is associated with a phenotypic switch of pulmonary arterial vascular smooth muscle cells (PASMCs). Bone morphogenetic protein (BMP) signaling and potassium two pore domain channel subfamily K member 3 (KCNK3) play crucial roles in PAH pathogenesis. However, the relationship between BMP signaling and KCNK3 expression in the PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expression and the role of KCNK3 in the BMP-mediated PASMC phenotypic switch. Expression levels of BMP receptor 2 (BMPR2) and KCNK3 were downregulated in PASMCs of rats with PAH compared to those in normal controls, implying a possible association between BMP/BMPR2 signaling and KCNK3 expression in the pulmonary vasculature. Treatment with BMP2, BMP4, and BMP7 significantly increased KCNK3 expression in primary human PASMCs (HPASMCs). BMPR2 knockdown and treatment with Smad1/5 signaling inhibitor substantially abrogated the BMP-induced increase in KCNK3 expression, suggesting that KCNK3 expression in HPASMCs is regulated by the canonical BMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3 knockdown and treatment with a KCNK3 channel blocker completely blocked BMP-mediated anti-proliferation and expression of contractile marker genes in HPAMSCs, suggesting that the expression and functional activity of KCNK3 are required for BMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signaling and KCNK3 in regulating the PASMC phenotype, wherein BMPs upregulate KCNK3 expression and KCNK3 then mediates BMP-induced phenotypic switching of PASMCs. Our results indicate that the dysfunction and/or downregulation of BMPR2 and KCNK3 observed in PAH work together to induce aberrant changes in the PASMC phenotype, providing insights into the complex molecular pathogenesis of PAH.

• The Korean Journal of Physiology and Pharmacology
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• 제24권1호
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• pp.111-119
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• 2020

In vascular smooth muscle, K⁺ channels, such as voltage-gated K⁺ channels (Kv), inward-rectifier K⁺ channels (Kir), and big-conductance Ca²⁺-activated K⁺ channels (BK_Ca), establish a hyperpolarized membrane potential and counterbalance the depolarizing vasoactive stimuli. Additionally, Kir mediates endothelium-dependent hyperpolarization and the active hyperemia response in various vessels, including the coronary artery. Pulmonary arterial hypertension (PAH) induces right ventricular hypertrophy (RVH), thereby elevating the risk of ischemia and right heart failure. Here, using the whole-cell patch-clamp technique, we compared Kv and Kir current densities (I_Kv and I_Kir) in the left (LCSMCs), right (RCSMCs), and septal branches of coronary smooth muscle cells (SCSMCs) from control and monocrotaline (MCT)-induced PAH rats exhibiting RVH. In control rats, (1) I_Kv was larger in RCSMCs than that in SCSMCs and LCSMCs, (2) I_Kv inactivation occurred at more negative voltages in SCSMCs than those in RCSMCs and LCSMCs, (3) I_Kir was smaller in SCSMCs than that in RCSMCs and LCSMCs, and (4) I_BKCa did not differ between branches. Moreover, in PAH rats, I_Kir and I_Kv decreased in SCSMCs, but not in RCSMCs or LCSMCs, and I_BKCa did not change in any of the branches. These results demonstrated that SCSMC-specific decreases in I_Kv and I_Kir occur in an MCT-induced PAH model, thereby offering insights into the potential pathophysiological implications of coronary blood flow regulation in right heart disease. Furthermore, the relatively smaller I_Kir in SCSMCs suggested a less effective vasodilatory response in the septal region to the moderate increase in extracellular K⁺ concentration under increased activity of the myocardium.

• Clinical and Experimental Pediatrics
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• 제53권2호
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• pp.195-202
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• 2010

목 적 : 본 연구에서는 좌우 단락에 의한 심한 폐동맥 고혈압으로 수술 가능 여부가 불확실했던 환자들의 수술 후 중기 임상 경과를 보고하고자 한다. 방 법 : 1995년 이후 삼성서울병원에서 좌우 단락에 의한 폐동맥 고혈압으로 심도자술 후 수술 받은 환자들 중, 만 1세 이후, 폐혈관 저항 8 Wood unit 이상이었던 21명의 환자를 대상으로 이들의 수술 전후 및 추적 기간 중 임상 증상, 폐동맥 압력 변화를 후향적으로 검토하였다. 대상 환자의 수술 당시 평균 연령은 26 (1-58)세였다. 진단은 심방 중격 결손(n=11), 심실 중격 결손(n=4), 심실 중격 결손과 동맥관 개존(n=4), 그리고 동맥관개존(n=2)이었다. 수술 여부는 폐혈관 가역성에 기초하여 결정하였으며, 5명에서는 좌우 단락을 완전히 막았고, 16명의 환자는 작은 좌우 단락을 남겨 놓는 형태의 수술을 시행 받았다. 결 과 : 수술 직후 폐동맥에 삽입한 도관이나 심초음파로 추정한 폐동맥 압력은 모든 환자에서 수술 전보다 감소되었다. 또한 이러한 수술 직후의 폐동맥 압력은 수술 전 결손의 일시적 폐쇄 당시의 폐동맥 압력과 유사한 값을 보였다. 두 명의 환자를 제외한 대부분 환자에서 추적 기간 동안 폐동맥 압력이 감소추세를 유지하였다. 임상증상은 NYHA functional class 기준으로 한 명의 환자를 제외하고는 모두 호전을 보였다. 수술 직후뿐만 아니라 추적 관찰 기간 동안에도 사망이나, 수술과 관련된 특별한 합병증은 없었다. 결 론 : 본 연구에서는 좌우 단락에 의한 심한 폐동맥 고혈압 환자들을 폐동맥 고혈압 가역성에 근거하여 수술하였고, 큰 위험 없이 심장 수술이 가능하였다. 폐동맥 확장제 흡입에 반응을 보이지 않았던 환자들에서 결손의 일시적 폐쇄 상태에서는 반응을 보인 경우가 많았고, 이는 수술 직후 폐동맥 압력과 유사하여 유용한 정보를 얻을 수 있었다. 대부분의 환자에서 폐동맥 압력이 감소하고 임상 양상의 호전을 보였으나, 다시 증가하거나 정상까지 감소하지 않을 수 있으므로 세심한 관찰과 장기적인 추적이 필요하다.

• Clinical and Experimental Pediatrics
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• 제59권6호
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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.

• Neonatal Medicine
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• 제16권2호
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• pp.146-153
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• 2009

목 적: 고식적인 치료에 반응하지 않는 기관지폐 이형성증에 대한 치료로서 덱사메타손 구제 치료의 사용현황을 조사하기 위해 본 연구를 시행하였다. 방 법: 2004년 3월부터 2008년 8월까지 서울대학교 어린이병원 및 분당서울대학교병원 신생아 중환자실에 입원하여 기관지폐 이형성증으로 치료를 받은 251례의 미숙아를 대상으로 후향적으로 연구하였다. 산모와 신생아들의 인구학적, 임상적 특성을 살펴보았으며, 덱사메타손 구제 치료의 반응성에 따라 반응군 및 비반응군간의 차이점을 비교 분석하였다. 또한 덱사메타손 구제 치료에 따른 합병증을 조사하였다. 결 과: 93례(37.1%)가 중증도의 기관지폐 이형성증으로 분류되었으며, 모든 덱사메타손 구제 치료는 중증도의 기관지폐 이형성증을 가진 사례에서 시행되었다. 덱사메타손은 고식적인 치료가 실패하여 기관 발관이 불가능한 호흡 곤란을 가진 24례(9.6%)에서 투여되었다. 투여된 사례 중 14례(58.3%)에서 덱사메타손 구제 치료에 반응을 나타냈다. 비반응군은 보다 많은 산소 공급을 요구하였으며 폐동맥 고혈압이 동반되는 경우가 많았다. 반응군은 입원 기간의 단축과 사망률의 감소 소견을 보였다. 고용량의 덱사메타손을 투여하는 것이 저용량에 비하여 보다 효과적으로 기계 환기에서 이탈을 유도한다는 근거는 도출되지 않았다. 패혈증은 덱사메타손 구제 치료 이후에 가장 빈번하게 발생하는 합병증이다. 결 론: 중증의 기관지폐 이형성증에서 폐동맥 고혈압이 발생하기 전에 덱사메타손 구제 치료를 시행하는 것이 치료 효과 측면에서 도움이 될 수 있다. 폐동맥 고혈압이 동반된 경우에는 합병증의 발생 가능성으로 인해 덱사메타손 구제 치료를 하지 않는 것이 바람직하다.