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CLINICAL RESEARCH: DISEASE OF THE AORTA

Early Growth Response Factor-1 Is Associated With Intraluminal Thrombus Formation in Human Abdominal Aortic Aneurysm

In-Soon Shin, MS^_*, Jeong-Min Kim, BS^_*, Koung Li Kim, MS^_*, Shin Yi Jang, PhD^_*, Eun-Seok Jeon, MD, PhD^_*, Seung Hyuk Choi, MD, PhD^_*, Duk-Kyung Kim, MD, PhD^_*, Wonhee Suh, PhD^,_* and Young-Wook Kim, MD, FACS^,_*

^_* Division of Cardiology, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
Department of Molecular and Life Science, Pochon CHA University, Seoul, Korea

Manuscript received June 13, 2008; revised manuscript received August 27, 2008, accepted October 20, 2008.

^_* Reprint requests and correspondence: Dr. Young-Wook Kim, Division of Vascular Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea (Email: wsuh{at}cha.ac.kr).

^_* Dr. Wonhee Suh, Department of Molecular and Life Science, Pochon CHA University, Yeoksam1-dong, Kangnam-ku, Seoul 135-907, Korea (Email: ywkim{at}skku.edu).

Objectives: The goal of this study was to investigate the expression of early growth response-1 (Egr-1), a vascular pathogenic transcription factor, and its potential relationship with tissue factor (TF), a key player during the thrombus formation in the abdominal aortic aneurysm (AAA) wall.

Background: Although intraluminal thrombus is a common finding in human AAA, the molecular mechanism of the thrombus formation has not been studied.

Methods: During the elective AAA repair, specimens were taken from the thrombus-covered and thrombus-free portions of the aneurysmal wall in each of 16 patients with AAA and analyzed to assess the differential expression of Egr-1 and TF. The proinflammatory and prothrombogenic activities of Egr-1 in vasculature were evaluated in vitro and in vivo by overexpressing it using adenovirus.

Results: The expression of both Egr-1 and TF was significantly increased in the thrombus-covered wall compared with the thrombus-free wall, in which their up-regulation in the thrombus-covered wall was strongly correlated with each other (p < 0.005, r = 0.717). Adenoviral overexpression of Egr-1 in human vascular smooth muscle and endothelial cells was found to up-regulate the expression of TF and inflammation-related genes. Moreover, Egr-1 overexpression in endothelial cells increased their adhesiveness to monocytes and also substantially promoted the intravascular thrombus formation in vivo, as shown in the inferior vena cava ligation experiment of the rat.

Conclusions: The present study demonstrates the differential up-regulation of Egr-1 in the thrombus-covered wall of human AAA and also suggests its possible contribution to the thrombogenic and inflammatory pathogenesis in human AAA.

Key Words: abdominal aortic aneurysm • thrombus • early growth response-1 • tissue factor

Abbreviations and Acronyms   AAA = abdominal aortic aneurysm   Egr = early growth response factor   HASMC = human aortic smooth muscle cell   HUVEC = human umbilical vein endothelial cell   ICAM = intercellular adhesion molecule   IVC = inferior vena cava   MCP = monocyte chemotactic protein   MIP = macrophage inflammatory protein   PBS = phosphate-buffered saline   RT-PCR = reverse transcriptase-polymerase chain reaction   TF = tissue factor

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