Activation of Endothelin-1 Receptor Signaling Pathways Is Associated With Neointima Formation, Neoangiogenesis and Irreversible Pulmonary Artery Hypertension in Patients With Congenital Heart Disease

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概要

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• Background: It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH. Methods and Results: The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n=6; irreversible PAH, n=10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH. Conclusions: Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities. (Circ J 2011; 75: 1463-1471)

• 2011-05-25

著者

• Wang Zhen

  Department Of Astronomy Nanjing University

• Zhang Peng

  Department Of Anesthesiology Qilu Hospital Affiliated With Shandong University

• HUANG HaiQiong

  Department of Anesthesiology, Zhongshan Hospital affiliated with Fudan University

• TANG Feng

  Department of Pathology, Huashan Hospital affiliated with Fudan University

• JIANG Zhen

  Department of Anesthesiology, Zhongshan Hospital affiliated with Fudan University

• Jiang Zhen

  Department Of Anesthesiology Zhongshan Hospital Affiliated With Fudan University

• Tang Feng

  Department Of Pathology Huashan Hospital Affiliated With Fudan University

• Wang Zhen

  Department Of Molecular Pathology Cleveland Clinic Pathology & Laboratory Medicine Institute And

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