이차성 폐동맥고혈압 환자 폐조직에서의 유전자 발현 양상에 관한 연구 = Different Gene Expression Patterns in the Lungs of Patients with Secondary Pulmonary Hypertension

다국어 초록 (Multilingual Abstract)

Background and Objectives: Despite the similar degree of pressure or volume overloading, the development of secondary pulmonary hypertension (PH) shows diverse variability among individual patients. Subjects and Methods: Using microarray technology, we compared the gene expression pattern of the lung tissues in 13 patients with secondary PH due to congenital shunt (pulmonary arterial hypertension, PAH, n=6) or valvular heart disease (pulmonary venous hypertension, PVH, n=7) with 5 normal subjects. Results: As compared to the normal controls, secondary PH showed a decreased expression of genes encoding transcriptional factors (BHLHB2, EGR3, JUNB, KLF4, KLF6 and MAFF), cytoskeleton protein (VIL2 and XLKD1) and cell differentiation and viability (MCL1, SNF1LK and TNFAIP3). PVH showed an increased expression of genes encoding proliferation of pulmonary capillary endothelial cells (ESM1), cell proliferation (IGFBP2 and BMP6), collagen synthesis (COL4A2 and SERPINH1), and cytoskeleton (TMSL8) as compared with the normal controls. In patients with secondary PH, PVH showed an upregulated expression of proliferation of pulmonary capillary endothelial cells (ESM1), cell proliferation (EGR2, PLK2 and TNC) and collagen synthesis (COL4A1), and an down-regulated expression of inflammation (IL1RL1, IL7R, CCL5, CCL19, CXCR 6 and XCL1/XCL2) and immune response (IGHM and TRA@; TRAC), as compared with PAH. Conclusion: There were significant differences in the gene expression pattern in secondary PH patients according to the underlying mechanism. A future study is needed to determine the diagnostic and therapeutic implications of these findings. (Korean Circ J 2008;38:51-59)

국문 초록 (Abstract)

배경 및 목적다양한 심질환에서 동일한 정도의 압력과 용적부하에도 불구하고 이차성 폐동맥고혈압의 발생 및 증등도는 매우 다양하다. 연구자는 이차성 폐동맥고혈압이 발생한 환자의 폐조직 분석을 통하여 원인질환에 따라 발현되는 유전자의 차이를 비교하였다.방 법전체 13명의 이차성 폐동맥고혈압 환자에서 gene microarray를 통하여 폐조직이 분석되었으며 원인질환에 따라 용적과부하형인 폐동맥고혈압 (심실중격결손 2명, 심방중격결손 4명) 환자가 6명, 압력과부하형인 폐정맥고혈압 (승모판부전증 4명, 승모판협착증 1명, 대동맥판부전증 1명, 승모판 및 대동맥판 부전증 1명) 환자가 7명이었다. 이차성 폐동맥고혈압 환자의 폐조직은 정상 대조군 5명의 폐조직 유전자와 비교 분석되었다.
결 과
이차성 폐동맥고혈압 환자군과 정상 대조군과의 비교에서 다양한 유전자 발현 형태가 관찰되었을 뿐만 아니라 발생기전에 따라서도 서로 다른 유전자 발현 형태를 관찰할 수 있었다. 정상 대조군에 비하여 폐동맥고혈압이 발생한 환자에서 발현 감소된 유전자는 주로 DNA 전사와 관련된 인자 (BHLHB2, EGR3, JUNB, KLF4, KLF6, MAFF), 세포 골격 형성 (VIL2, XLKD1), 세포 분화 및 유지 (MCL1, SNF1LK, TNFAIP3)와 관련되었다. 정상 대조군에 비하여 폐동맥고혈압 환자군에서 발현 증가된 유전자는 없었으며, 이에 반하여 폐정맥고혈압 환자군에서 발현 증가된 유전자는 폐모세혈관의 증식 (ESM1), 세포성장 (IGFBP2), 콜라겐 증식 (COL4A2, SERPINH1), 세포골격 (TMSL8) 관련 유전자였다. 폐동맥고혈압에 비하여 폐정맥고혈압에서 발현 증가된 유전자는 주로 콜라겐 형성 (COL1A1), 세포 및 혈관증식 (EGR2, ESM1)과 관련되었으며, 발현 감소된 유전자는 주로 면역 및 염증반응 (IL1RL1, CCL19), 세포방어 (SH2D1A) 관련 유전자들이었다.
결 론
여러 심장질환에 의한 이차성 폐동맥고혈압 환자에서의 폐조직 유전자 발현 양상은 정상군과 비교하여 서로 다른 발현 형태를 보였으며 폐동맥고혈압 유발기전에 따라서도 서로 다른 발현을 관찰할 수 있었다. 이러한 차이의 임상적 의미와 병태생리학적 기전과의 연관성 여부는 향후 더 많은 연구가 필요할 것으로 판단된다.

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