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J Thorac Cardiovasc Surg 2001;122:65-73
© 2001 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease (ACD)

Human angiopoietin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarterectomy

From the Division of Cardiothoracic Surgery, University of California, San Diego,^a the Department of Pathology, Veterans Affairs Medical Center,^b and the Department of Family and Preventive Medicine, University of California, San Diego, Calif.^c

This study was supported in part by the Maurice and Charmaine Kaplan Foundation (Patricia A. Thistlethwaite, MD, PhD) and the Thoracic Surgery Foundation Research Fellowship (Sang H. Lee, MD).

Received for publication Aug 8, 2000. Revisions requested Sept 27, 2000; revisions received Nov 29, 2000. Accepted for publication Dec 1, 2000. Address for reprints: Patricia A. Thistlethwaite, MD, PhD, Assistant Professor of Surgery, Cardiothoracic Surgery, University of California, San Diego, 200 West Arbor Dr, San Diego, CA 92103-8892 (E-mail: pthistlethwaite{at}ucsd.edu).

Abstract

Objective: A consistent pathologic feature seen in lungs of patients with pulmonary hypertension from thromboembolic disease is hyperplasia of the media of pulmonary arterioles. The molecular factors responsible for these vessel wall changes are unknown. Angiopoietin-1 is a gene responsible for the formation of the media of blood vessels in utero. We hypothesized that aberrant expression of the angiopoietin-1 gene in the adult lung would be a major contributing factor in the development of pulmonary hypertension.
Methods: From April 1999 to March 2000, a total of 35 patients (18 men, 17 women, mean age 52 years) with pulmonary hypertension and pulmonary vascular resistance ranging from 407 to 2006 dynes · sec · cm^–5 underwent pulmonary endarterectomy at our institution. Before cardiopulmonary bypass, lung biopsy specimens were taken from each patient. Biopsy specimens were also obtained from 10 patients (5 women, 5 men, mean age 55 years) undergoing lung resection for causes other than pulmonary hypertension. All specimens were blindly scored by a pathologist for degree of medial hyperplasia. Quantitative reverse transcriptase–polymerase chain reaction, Western blot, and immunohistochemistry were used to quantitate angiopoietin-1 messenger RNA and protein in each sample.
Results: Lung specimens from all patients with pulmonary hypertension demonstrated up-regulation of angiopoietin-1 at the messenger RNA level. The degree of angiopoietin-1 transcription was directly proportional to the preoperative pulmonary vascular resistance and medial wall hyperplasia/hypertrophy in each patient. By immunohistochemistry, angiopoietin-1 protein was confined to the media of pulmonary arterioles. Lung biopsy specimens from patients without pulmonary hypertension had no detectable expression of angiopoietin-1 at the messenger RNA or protein level.
Conclusion: Angiopoietin-1, a gene responsible for vessel development in the embryonic lung, is up-regulated in the lung parenchyma of patients with pulmonary hypertension. The level of expression of angiopoietin-1 at messenger RNA and protein levels correlates to the severity of pulmonary hypertension in patients with thromboembolic disease and serves as a target for strategies to treat this disease.

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