Prevention of pulmonary hypertension by Angiotensin-converting enzyme 2 gene transfer.

Abstract

In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline (MCT) treatment of mice for 8 weeks resulted in significant increases in right ventricular systolic pressure, right ventricle:left ventricle plus septal weight ratio, and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2, 7 days before MCT treatment prevented the increases in right ventricular systolic pressure (control: 25+/-1 mm Hg; MCT: 44+/-5 mm Hg; MCT+ACE2: 26+/-1 mm Hg; n=6; P<0.05) and right ventricle:left ventricle plus septal weight ratio (control: 0.25+/-0.01; MCT: 0.31+/-0.01; MCT+ACE2: 0.26+/-0.01; n=8; P<0.05). A significant attenuation in muscularization of pulmonary vessels induced by MCT was also observed in animals overexpressing ACE2. These beneficial effects were associated with an increase in the angiotensin II type 2 receptor:angiotensin II type 1 receptor mRNA ratio. Also, pulmonary hypertension-induced increases in proinflammatory cytokines were significantly attenuated by lentiviral vector-containing ACE2 treatment. Furthermore, ACE2 gene transfer in mice after 6 weeks of MCT treatment resulted in a significant reversal of right ventricular systolic pressure. These observations demonstrate that ACE2 overexpression prevents and reverses right ventricular systolic pressure and associated pathophysiology in MCT-induced pulmonary hypertension by a mechanism involving a shift from the vasoconstrictive, proliferative, and fibrotic axes to the vasoprotective axis of the renin-angiotensin system and inhibition of proinflammatory cytokines.

• Authors: Yoriko Yamazato, Anderson J Ferreira, Kwon-Ho Hong, Srinivas Sriramula, Joseph Francis, Masanobu Yamazato, Lihui Yuan, Chastity N Bradford, Vinayak Shenoy, Suk P Oh, Michael J Katovich, Mohan K Raizada
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 54 Issue 2 Pg. 365-71 (Aug 2009) ISSN: 1524-4563 [Electronic] United States
• PMID: 19564552 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• RNA, Messenger
• Monocrotaline
• Peptidyl-Dipeptidase A
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2

Topics

• Analysis of Variance
• Angiotensin-Converting Enzyme 2
• Animals
• Disease Models, Animal
• Gene Transfer Techniques
• Hypertension, Pulmonary (chemically induced, prevention & control)
• Infusions, Subcutaneous
• Male
• Mice
• Mice, Inbred C57BL
• Monocrotaline (pharmacology)
• Peptidyl-Dipeptidase A (genetics, pharmacology)
• Probability
• RNA, Messenger (analysis)
• Random Allocation
• Renin-Angiotensin System (drug effects)
• Sensitivity and Specificity