• Molecules and Cells
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• 제40권1호
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• pp.66-72
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• 2017

Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit $(p-eIF2)-{\alpha}$, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal ($0.5mg{\cdot}kg^{-1}{\cdot}day^{-1}$) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

• Molecules and Cells
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• 제44권7호
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• pp.500-516
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• 2021

Cardiac hypertrophic signaling cascades resulting in heart failure diseases are mediated by protein phosphorylation. Recent developments in mass spectrometry-based phosphoproteomics have led to the identification of thousands of differentially phosphorylated proteins and their phosphorylation sites. However, functional studies of these differentially phosphorylated proteins have not been conducted in a large-scale or high-throughput manner due to a lack of methods capable of revealing the functional relevance of each phosphorylation site. In this study, an integrated approach combining quantitative phosphoproteomics and cell-based functional screening using phosphorylation competition peptides was developed. A pathological cardiac hypertrophy model, junctate-1 transgenic mice and control mice, were analyzed using label-free quantitative phosphoproteomics to identify differentially phosphorylated proteins and sites. A cell-based functional assay system measuring hypertrophic cell growth of neonatal rat ventricle cardiomyocytes (NRVMs) following phenylephrine treatment was applied, and changes in phosphorylation of individual differentially phosphorylated sites were induced by incorporation of phosphorylation competition peptides conjugated with cell-penetrating peptides. Cell-based functional screening against 18 selected phosphorylation sites identified three phosphorylation sites (Ser-98, Ser-179 of Ldb3, and Ser-1146 of palladin) displaying near-complete inhibition of cardiac hypertrophic growth of NRVMs. Changes in phosphorylation levels of Ser-98 and Ser-179 in Ldb3 were further confirmed in NRVMs and other pathological/physiological hypertrophy models, including transverse aortic constriction and swimming models, using site-specific phospho-antibodies. Our integrated approach can be used to identify functionally important phosphorylation sites among differentially phosphorylated sites, and unlike conventional approaches, it is easily applicable for large-scale and/or high-throughput analyses.

• 생명과학회지
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• 제17권12호
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• pp.1717-1722
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• 2007

12주간의 저강도 트레드밀 운동은 본태성 고혈압 쥐의 안정시 심박수와 혈압, LPOA와 호모시스테인 수준의 개선과 함께 심장근의 eNOS mRNA 및 골격근의 sNOS 단백질 발현량을 증가시킨 반면 심근의 ET-1 mRNA 수준을 감소시키는 것으로 나타났다. 이러한 결과들은 결국 운동이 혈압조절 뿐만 아니라 고혈압에 의한 심근비대현상 관련 유전자들의 기능개선을 가져와 고혈압을 개선시키는 작용을 한다는 것을 확인 할 수 있었다.

• BMB Reports
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• 제56권6호
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• pp.341-346
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• 2023

Acute myocardial infarction (AMI) is a multifaceted syndrome influenced by the functions of various extrinsic and intrinsic pathways and pathological processes, which can be detected in circulation using biomarkers. In this study, we investigated the secretome protein profile of induced-hypertrophy cardiomyocytes to identify next-generation biomarkers for AMI diagnosis and management. Hypertrophy was successfully induced in immortalized human cardiomyocytes (T0445) by 200 nM ET-1 and 1 μM Ang II. The protein profiles of hypertrophied cardiomyocyte secretomes were analyzed by nano-liquid chromatography with tandem mass spectrometry and differentially expressed proteins that have been identified by Ingenuity Pathway Analysis. The levels of 32 proteins increased significantly (>1.4 fold), whereas 17 proteins (<0.5 fold) showed a rapid decrease in expression. Proteomic analysis showed significant upregulation of six 14-3-3 protein isoforms in hypertrophied cardiomyocytes compared to those in control cells. Multi-reaction monitoring results of human plasma samples showed that 14-3-3 protein-zeta levels were significantly elevated in patients with AMI compared to those of healthy controls. These findings elucidated the role of 14-3-3 protein-zeta in cardiac hypertrophy and cardiovascular disorders and demonstrated its potential as a novel biomarker and therapeutic strategy.

• Korean Circulation Journal
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• 제54권4호
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• pp.172-186
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• 2024

Background and Objectives: Long-term pathological myocardial hypertrophy (MH) seriously affects the normal function of the heart. Dronedarone was reported to attenuate left ventricular hypertrophy of mice. However, the molecular regulatory mechanism of dronedarone in MH is unclear. Methods: Angiotensin II (Ang II) was used to induce cell hypertrophy of H9C2 cells. Transverse aortic constriction (TAC) surgery was performed to establish a rat model of MH. Cell size was evaluated using crystal violet staining and rhodamine phalloidin staining. Reverse transcription quantitative polymerase chain reaction and western blot were performed to detect the mRNA and protein expressions of genes. JASPAR and luciferase activity were conducted to predict and validate interaction between forkhead box O3 (FOXO3) and protein kinase inhibitor alpha (PKIA) promoter. Results: Ang II treatment induced cell hypertrophy and inhibited sirtuin 1 (SIRT1) expression, which were reversed by dronedarone. SIRT1 overexpression or PKIA overexpression enhanced dronedarone-mediated suppression of cell hypertrophy in Ang II-induced H9C2 cells. Mechanistically, SIRT1 elevated FOXO3 expression through SIRT1- mediated deacetylation of FOXO3 and FOXO3 upregulated PKIA expression through interacting with PKIA promoter. Moreover, SIRT1 silencing compromised dronedarone-mediated suppression of cell hypertrophy, while PKIA upregulation abolished the influences of SIRT1 silencing. More importantly, dronedarone improved TAC surgery-induced MH and impairment of cardiac function of rats via affecting SIRT1/FOXO3/PKIA axis. Conclusions: Dronedarone alleviated MH through mediating SIRT1/FOXO3/PKIA axis, which provide more evidences for dronedarone against MH.

• Biomolecules & Therapeutics
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• 제28권5호
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• pp.482-489
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• 2020

G protein-coupled receptor kinase 5 (GRK5) has been considered as a potential target for the treatment of heart failure as it has been reported to be an important regulator of pathological cardiac hypertrophy. To discover novel scaffolds that selectively inhibit GRK5, we have identified a novel small molecule inhibitor of GRK5, KR-39038 [7-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-2-(2-chlorophenyl)-6-fluoroquinazolin-4(3H)-one]. KR-39038 exhibited potent inhibitory activity (IC₅₀ value=0.02 µM) against GRK5 and significantly inhibited angiotensin II-induced cellular hypertrophy and HDAC5 phosphorylation in neonatal cardiomyocytes. In the pressure overload-induced cardiac hypertrophy mouse model, the daily oral administration of KR-39038 (30 mg/kg) for 14 days showed a 43% reduction in the left ventricular weight. Besides, KR-39038 treatment (10 and 30 mg/kg/day, p.o.) showed significant preservation of cardiac function and attenuation of myocardial remodeling in a rat model of chronic heart failure following coronary artery ligation. These results suggest that potent GRK5 inhibitor could effectively attenuate both cardiac hypertrophy and dysfunction in experimental heart failure, and KR-39038 may be useful as an effective GRK5 inhibitor for pharmaceutical applications.

• 대한관절경학회지
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• 제5권2호
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• pp.63-68
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• 2001

목적 : 전방 십자 인대의 비후라는 진단명과 이에 대한 임상적, 방사선학적 및 병리학적인 특징들을 제시하고자 하였다. 대상 및 방법 : 1995년 12월 이후 전방 십자 인대의 비후가 주진단으로 생각되었던 10명(12례)의 환자를 대상으로 하였다. 남자가 2명, 여자가 8명이었으며 연령은 35세에서 67세까지였다. 임상적, 방사선학적 및 병리학적 소견들을 분석하여 그 특징을 알아보았다. 결과 : 주증상은 특별한 외상병력이 없이 활동에 의해 악화되는 슬관절의 둔통이었으며 이학적 검사상 동통으로 인한 슬관절 완전 신전의 제한이 있었다. 자기공명 시상면 영상에서 전방십자인대가 신호강도의 증가를 동반한 미만성 종창 또는 비후를 보여 전방 십자 인대의 급성 파열시 관찰될 수 있는 소견과 비슷하였다. 관절경 검사에서 전방십자인대가 심하게 비후되어 슬관절 완전 신전시 대퇴과간 절흔과의 충돌현상을 관찰할 수 있었다. 병리학적 소견상 교원질의 증가 및 점액양 변성(myxoid degeneration)이 관찰되었다. 비후된 전방 십자 인대의 부분 절제술 및 절흔 성형술(notchplastry)로 동통 및 운동제한이 소실되었다. 결론 : 슬관절 동통을 유발시킬 수 있는 원인중의 하나로 "전방 십자 인대의 비후"라는 새로운 진단명을 제시하는 바이며, 향후 본 증례들의 발생원인을 규명하기 위한 연구가 더 필요할 것으로 생각된다.

• 한국동물위생학회지
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• 제22권1호
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• pp.25-35
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• 1999

The prevalence of canine heartworm(Dirofilaria immitis) infection in 150 mixed-breed dogs(male : 54, female : 96) from February to December 1997 was investigated by using antigen test kit(ICT $GOLD^{TM}$ HW, Synbiotics, USA) based on immunochromatographic assay in Inchon city. Also, gross and histopathological findings of an antigen positive dog were carried out. The results were summarized as follows ; 1. Four dogs were positive from 150 tested dogs(2.7%). They were all more than 2 years old and infection rates in male and outdoor dogs was higher than those in female and indoor, respectively. Species of infected dogs were Pug(2) , German Sheperd(1) and Great-dane (1). 2. Regional infection rates were closely related with housing system in the city. 3. Pathological findings of antigen-positive dog was excessive enlargement, congestion and hemorrhage of lung and D immitis in heart and histologically hemosiderin, hypertrophy of pulmonary alveoli wall and irregular hypertrophy of pulmonary artery inner wall. Microfilaria was observed in pulmonary artery and arteriole, ventricle and splenic artery.

• 한국동물위생학회지
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• 제46권4호
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• pp.363-368
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• 2023

Patent ductus arteriosus (PDA) in monkeys is very rare. A 9-year-old male Japanese macaque (Macaca fuscata) had an hourglass-shaped PDA with a large luminal diameter. Morphological analysis of the vessel cast and heart revealed cardiovascular pathological changes including pulmonary artery hypertension and right ventricular hypertrophy. However, left ventricle hypertrophy or left atrial enlargement were not observed. This macaque had showed no clinical signs of PDA during its lifetime. We present the first documented case of solitary PDA in a male macaque.

• 수산해양교육연구
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• 제24권5호
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• pp.609-615
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• 2012

A histo-pathogical examination was carried out to evaluate the effect of commercial extruded pellet (EP) and a raw fish moist pellet (MP) diet on the health of juvenile rockfish cultured in marine net-cage for 7 months. Fish were distributed randomly to each net cage as a group of 76,000 fish (initial mean body weight 5.9 g). After 2 months, the hypertrophy or swelling of liver parenchymal cells was identified in most individuals and lasted until 7 months. Livers in EP fed group frequently showed hypertrophic parenchyma and fatty change with occasional atrophic cells. However, after 4 months, lymphocytic infiltration in splenic parenchyma was seen in a number of individuals. In addition, the gastric glandular epithelium was atrophied and in the lumen of renal tubules protozoan parasites were frequently identified but there was no correlation with the type of feed. Moreover, juvenile rockfish on EP diet showed gross and microscopic hypertrophy of the liver which would be due to oversupply of feed. Severe hepatic cellular hypertrophy or swelling could lead to the damage of microcirculation. Especially fatty change and atrophic change of liver could be the result from the damage, which could be responsible for immunological problem. Lymphocytic infiltration of spleen on the MP diet suggests that juvenile rockfish could be frequently exposed to infectious antigens.