Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappaB and AP-1.

Abstract

The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor-alpha (TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 +/- 2.5 mmHg (P < 0.05) vs. 15.2 +/- 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NF-kappaB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 +/- 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly (P < 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NF-kappaB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.

• Authors: Luis A Ortiz, Hunter C Champion, Joseph A Lasky, Federica Gambelli, Evelyn Gozal, Gary W Hoyle, Mary B Beasley, Albert L Hyman, Mitchell Friedman, Philip J Kadowitz
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 282 Issue 6 Pg. L1209-21 (Jun 2002) ISSN: 1040-0605 [Print] United States
• PMID: 12003776 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antihypertensive Agents
• Collagen Type I
• NF-kappa B
• RNA, Messenger
• Receptors, Tumor Necrosis Factor
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• Bleomycin
• Enalapril

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Bleomycin
• Body Weight (drug effects)
• Cardiac Output (drug effects)
• Collagen Type I (genetics, metabolism)
• Disease Models, Animal
• Enalapril (pharmacology)
• Female
• Gene Expression (drug effects)
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (chemically induced, pathology, physiopathology, prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Pneumonia (chemically induced, metabolism, pathology)
• Pulmonary Circulation (drug effects)
• RNA, Messenger (metabolism)
• Receptors, Tumor Necrosis Factor (metabolism)
• Specific Pathogen-Free Organisms
• Transcription Factor AP-1 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)