Mechanisms of Platelet Activation and Integrin αIIβ3

주승재 대한심장학회 2012 Korean Circulation Journal Vol.42 No.5

Platelet aggregation is not only an essential part of hemostasis, but also initiates acute coronary syndrome or ischemic stroke. The precise understanding of the activation mechanism of platelet aggregation is fundamental for the development of more effective agents against platelet aggregation. Adenosine diphosphate, thrombin, and thromboxane A2 activate platelet integrin αIIbβ3 through G protein-coupled receptors. G protein-mediated signaling pathways, which are initiated by Gq, G12/G13 or Gi, include phospholipase C with calcium signaling,Rho signaling, protein kinase C and phosphatidylinositol 3-kinase. Rap1b, Ca2+ and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin αIIbβ3. Binding of talin-1 and kindlin-3 to cytoplasmic domains of β3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. Fibrinogens act as bridges between adjacent platelets to generate a platelet aggregate.

ADP에 의해서 활성화된 인혈관세포의 Prothrombin과 골타액단백 부착에 관여하는 Integrin αvβ3, αvβ5, α5β1의 특성

주승재,최휘,김성만,차태준,이재우 고신대학교(의대) 고신대학교 의과대학 학술지 2003 고신대학교 의과대학 학술지 Vol.18 No.1

Background : One of the most important features of integrins is that they exist in active and inactive states. Adenosine diphosphate (ADP), which is usually secreted from activated platelets, may activate integrins on vascular cells. Each integrin has its own activation-dependent ligands that have much higher affinity to active form than inactive one. Integrins that might mediate adhesion of human vascular cells to prothrombin (PT) and bone sialoprotein (BSP) after ADP stimulation were investigated. Methods : PT and BSP were used as activation-dependent ligands in adhesion assay. Adhesions of human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HASMC) were measured after stimulating with 100 μM of ADP, using ligand-coated 24-well plate and Fluorescence Multi-Well Plate Reader. Results : ADP activated HUVEC and HASMC to increase adhesions to PT and BSP in a dose-dependent manner. Adhesions of ADP-stimulated HUVEC to PT and BSP were almost completely inhibited by c7E3, a blocking monoclonal Ab to integrin β3 (96% and 92% inhibition, respectively), but not by P5H9, a blocking monoclonal Ab to integrin αvβ5. Adhesion of ADP-stimulated HASMC to PT was completely blocked by P5H9 (92% inhibition), but was not affected by c7E3. Adhesion of ADP-stimulated HASMC to BSP was partially inhibited either by P5H9 (46% inhibition) or by JBS5, a blocking monoclonal Ab to integrin α5β1 (75% inhibition), but was not affected by c7E3. However, it was completely blocked by cRGD (93% inhibition). Conclusion : These results indicate that the adhesion of ADP-stimulated HUVEC to PT or BSP was mediated by integrin αvβ3, and several integrins appeared to be involved in the adhesion of ADP-stimulated HASMC. While the adhesion of HASMC to PT was mediated by integrin αvβ5, the adhesion to BSP was associated with integrins αvβ5 and α5β1.

급성 심근경색 후 예후 인자로 사용될 수 있는 폐정맥 혈류의 도플러 심초음파 지표

주승재,이재우 대한순환기학회 2003 Korean Circulation Journal Vol.33 No.6

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

주승재 대한심장학회 2012 Korean Circulation Journal Vol.42 No.9

한국 약사제도(藥事制度)의 변천

주승재,주경식 대한약학회 2014 약학회지 Vol.58 No.6

The history of pharmaceutical service system in Korea originated from the beginning of Korean people was reviewed with focus on the pharmaceutical administration and laws after the Liberation from Japan in 1945.

ADP에 의해서 활성화된 인혈관세포의 Prothrombin과 골타액단백 부착에 관여하는 Integrin avβ3, avβ5, a5β1의 특성

주승재,최휘,김성만,차태준,이재우 고신대학교 의학부 2003 高神大學校 醫學部 論文集 Vol.18 No.1

Background : One of the most important features of integrins is that they exist in active and inactive states. Adenosine diphosphate (ADP), which is usually secreted from activated platelets, may activate integrins on vascular on vascular cells. Each integrin has its own activation-dependent ligands that have much higher affinity to active form than inactive one. Integrins that might mediate adhesion of human vascular cells to prothrombin(PT) and bone sialoprotein (BSP) after ADP stimulation were investigated. Methods : PT and BSP were used as activation-dependent ligands in adhesion assay. Adhesions of human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HASMC) were measured after stimulating with 100 μM of ADP, using ligand-coated 24-well plate and Fluorescence Multi-Well Plate Reader. Results : ADP activated HUVEC and HASMC to increase adhesions to PT and BSP in a dose-dependent manner. Adhesions of ADP-stimulated HUVEC to PT and BSP were almost completely inhibited by c7E3, a blocking monoclonal Ab to integrin β₃(96% and 92% inhibition, respectively), but not by P5H9, a blocking monoclonal Ab to integrin α_vβ_5. Adhesion of ADP-stimulated HASMC to PT was completely blocked by P5H9 (92% inhibition), but was not affected by c7E3. Adhesion of ADP-stimulated HASMC to BSP was partially inhibited either by P5H9 (46% inhibition) or by JBS5, a blocking monoclonal Ab to integrin inhibition), but was not affected by c7E3. However, it was completely blocked by cRGD (93% inhibition). Conclusion : These results indicate that the adhesion of ADP-stimulated HUVEC to PT or BSP was mediated by integrin α_vβ₃ and several integrins appeared to be involved in the adhesion of ADP-stimulated HASMC. While the adhesion of HASMC to PT was mediated by integrin α_vβ_5, the adhesion to BSP was associated with integrins α_vβ_5 and α_5β₁.

Statin이 ADP에 의해서 활성화된 대동맥평활근 세포의증식과 부착에 미치는 영향

주승재,이수창,이재우 대한심장학회 2006 Korean Circulation Journal Vol.36 No.12

Background and Objectives:Integrins mediate the migration, adhesion and proliferation of vascular smooth musclecells. Adenosine diphosphate (ADP) can activate vascular integrins. We assessed the hypothesis that ‘statinsinhibit the ADP-stimulated activation of integrins αvβ5 and αvβ3 in human aortic smooth muscle cells(HASMC)’. Materials and Methods:The expressions of integrins were analyzed using flow cytometry. The activationsof integrins were evaluated using the adhesion assay, with prothrombin as an activation-dependent ligand. TheMTT assay was used to evaluate the proliferation. Results:Statins did not suppress the expressions of the integrins,αvβ5 and αvβ3. The ADP-stimulated adhesion was partially prevented by LM609, which blocked integrin αvβ3(13% inhibition), and markedly prevented by P1F5, which blocked integrin αvβ5 (76% inhibition; n=5, p<0.05).However, the proliferation was inhibited by c7E3 and LM609, but not by P1F5. Statins inhibited the ADP-stimulatedadhesions in a dose-dependent manner after 15 min of pretreatment. After incubating HASMC with statins for1 day, simvastatin and fluvastatin inhibited the adhesion by 70 and 66%, respectively (n=5, p<0.05 vs. no statin).Statins also inhibited the ADP-stimulated proliferation of HASMC. Conclusion:Statins did not suppress the expressionsof the integrins, αvβ5 and αvβ3, but did inhibit the ADP-stimulated activation of the integrins of HASMC.(Korean Circulation J 2006; 36:809-816) 배경 및 목적:Integrin은 혈관 평활근세포의 이동, 부착, 증식 등을 매개하며 adenosine diphosphate(ADP)는 혈관 integrin을 활성화시킬 수 있다. 이 연구에서는 statin이 사람 대동맥평활근세포(human aortic smooth muscle cell: HASMC)에 있는integrin αvβ3와 αvβ5의 발현과 ADP에 의한 HASMC의 증Seung-Jae Joo, et al:Statins and Vascular Smooth Muscle Cells·815식과 부착에 미치는 영향을 구명하고자 하였다.방 법:유세포분석기를 이용하여 statin이 HASMC의 integrinαvβ3와 αvβ5의 발현에 미치는 영향을 측정하였다. MTT assay를이용하여 세포 증식 정도를 측정하였고, prothrombin부착 정량을 이용하여 integrin αvβ3와 αvβ5의 활성화 상태를 분석하였다. 결 과: Statin은 integrin αvβ3와 αvβ5의 발현에 영향을 미치지 않 았다. ADP에 의한 HASMC의 부착은 integrin αvβ3 차단항 체인 LM609에 의해서 13% 억제되었지만 integrin αvβ5 차 단항체인 P1F5에 의해서는 76% 억제되었다(n=5, p<0.05). 그 러나 HASMC의 증식은 c7E3와 LM609에 의해서만 억제되 었다(88%; n=4, p<0.05). HASMC의 부착은 simvastatin과 fluvastatin을 15분간 전처치 한 후에 10 μM의 농도에서는 각각 15%와 27%, 100 μM에서는 각각 45%와 72% 억제되었 으며(n=5, p<0.05), 5 μM의 농도로 24시간 배양한 후에는 각각 70%와 66% 억제되었다(n=5, p<0.05). ADP에 의한 HASMC의 증식은 statin에 의해서 농도에 비례하여 억제되었다. 결 론: Simvastatin과 fluvastatin은 integrin αvβ3와 αvβ5의 발현에는 영향을 미치지 않았지만 ADP에 의한 활성화에 영향을 미쳐서 HASMC의 증식과 부착을 억제하였다.

『세종실록』을 통해 본 고려인삼

주승재,Joo, Seungjae 고려인삼학회 2021 인삼문화 Vol.3 No.-

고려인삼은 대한민국의 대표적 특산 약용작물로 오래전부터 중국·일본을 비롯한 동아시아 교역에서 대표적인 품목이었다. 조선의 인삼 교역은 국가가 전적으로 통제한 공무역이었으므로 『조선왕조실록』은 조선의 삼업 역사를 조명할 수 있는 귀중한 자료이다. 역대 실록 중 인삼이 월등히 많이 쓰인 『세종실록』을 통하여 15세기 당시 고려인삼의 교역이 어떤 용도와 규모로 이루어졌는지 알아보고 『세종실록』 지리지에 기재된 당시 인삼의 자생지를 찾아 그 분포를 지도상에 표시해 보았다. 세종 재위 기간(1418~1450) 인삼을 중국에 진헌품으로 보낸 횟수는 101회, 규모는 11,000근(7,060.9kg1))으로 압도적인 교역량을 자랑하며, 일본과 유구국에도 예물 및 답례품으로 보냈으나 명 교역의 3분의 1이 안되었고 기타 외국 사절과 신하에게 하사하거나 유학생의 여비로 쓰이기도 했다. 재위 연도별로 보면, 중기 이후에 점차 줄어드는 경향을 보이는데 이는 채삼량 감소가 주된 원인으로 보인다. 『세종실록』 지리지에 기재된 당시 고려인삼의 자생지는 공물(土貢) 항목에 기록된 12곳-지금의 경북 영덕군, 영주시, 청송군/경남 울산시 울주군/전북 정읍시, 완주군, 장수군/전남 화순군/황북 곡산군·신평군/평북 정주시 일대, 태천군/자강도 자성군·중강군-과 약재(藥材) 항목에 기록된 산지 101곳 등 총 113개 지역으로, 도서지방을 제외한 조선 8도 전역에 걸쳐있었는데 모두 산을 끼고 분포하고 있었다. 또한, 현재 인삼재배지와 비교해 본 결과, 대체로 자생지와 일치하거나 인접한 지역이었다. 야생삼이 많이 나던 세종 재위 초(1432년)에 편찬된 『세종실록』 지리지의 이와 같은 기록들은 향후 한반도 인삼, 특히 산양삼 재배의 가능성을 보여주는 자료이다. 온난화로 인하여 인삼 재배지가 점차 북쪽으로 이동하는 이때, 역사 기록에 나타나는 북한의 자생지는 산양삼 재배의 좋은 후보지가 될 수 있을 것이다. Korean ginseng is the one of the most famous medicinal herbs globally and has long been a representative item of East Asian trade, including across China and Japan. Since Joseon (1392-1910) ginseng trade was entirely controlled by the state, The Veritable Records of the Joseon Dynasty are a valuable resource that can shed light on the history of the ginseng industry at that time. By studying the subsection "The Veritable Records of King Sejong" (世宗實錄), when ginseng was used even more widely, we assess the purpose and scale of its trade in the 15th century, identify its original listing in the geographical appendix, develop a distribution map, and explore similarities to current ginseng cultivation areas. During the reign of King Sejong (1418-1450), ginseng was sent to China as a tribute 101 times, with a combined weight of 7,060 kilograms, with less than one-third of that amount given to Japan and Okinawa. It was used to cover the travel expenses of foreign envoys and servants, but this can be seen to gradually decrease after the regnal mid-term, primarily due to a decrease in the amount of ginseng being collected. At the time, there were 113 areas of naturally growing ginseng as listed in the records' geographical appendix, including 12 recorded in the 'tributes' category: Yeongdeok-gun, Yeongju, and Cheongsong-gun in Gyeongsangbuk-do; Ulju-gun and Ulsan in Gyeongsangnam-do; Jeongeup, Wanju-gun, and Jangsu-gun in Jeollabuk-do; Hwasun-gun in Jeollanam-do; Goksan-gun and Sinpyeong-gun in Hwanghaebuk-do; Jeongju and Taecheon-gun in Pyeonganbuk-do; and Jaseong-gun and Junggang-gun in Jagang-do. A total of 101 places are recorded in the 'medicinal herbs' category, located throughout the mountains of the eight Joseon provinces, except the islands. In comparison with current ginseng cultivation sites, many of these historical areas are either consistent with or adjacent to contemporary locations. The geographical appendix to "The Veritable Records of King Sejong" was compiled in the early days of the king's reign (1432) when there was a lot of wild ginseng. The appendix is a valuable resource that indicates the possibility of growing ginseng on the Korean Peninsula in the future. The apparently natural habitats in the south, where ginseng is not currently cultivated, could be candidates for the future. Moreover, areas in the north where ginseng has not been grown, except Kaesǒng, could be a good alternative under sustainable inter-Korean exchange should cultivation sites move north due to climate warming.

Beta-blocker therapy in patients with acute myocardial infarction: not all patients need it

주승재 대한중환자의학회 2023 Acute and Critical Care Vol.38 No.3

Most of the evidences for beneficial effects of beta-blockers in patients with acute myocardial infarction (AMI) were from the clinical studies published in the pre-reperfusion era when anti-platelet drugs, statins or inhibitors of renin-angiotensin-aldosterone system which are known to reduce cardiovascular mortality of patients with AMI were not introduced. In the reperfusion era, beta-blockers’ benefit has not been clearly shown except in patients with reduced ejection fraction (EF; ≤40%). In the era of the early reperfusion therapy for AMI, a number of patients with mildly reduced EF (>40%, <50%) or preserved EF (≥50%) become increasing. However, because no randomized clinical trials are available until now, the benefit and the optimal duration of oral treatment with beta-blockers in patients with mildly reduced or preserved EF are questionable. Registry data have not showed the association of oral beta-blocker therapy with decreased mortality in survivors without heart failure or left ventricular systolic dysfunction after AMI. In the Korea Acute Myocardial Infarction Registry-National Institute of Health of in-hospital survivors after AMI, the benefit of beta-blocker therapy at discharge was shown in patients with reduced or mildly reduced EF, but not in those with preserved EF, which provides new information about beta-blocker therapy in patients without reduced EF. However, clinical practice can be changed when the results of appropriate randomized clinical trials are available. Ongoing clinical trials may help to answer the unresolved issues of beta-blocker therapy in patients with AMI.

고콜레스테롤혈증 환자에서 활성화된 혈소판 Glycoprotein Ⅱb/Ⅲa의 증가

주승재,이재우,박양생 대한순환기학회 1998 Korean Circulation Journal Vol.28 No.12