Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappaB and AP-1.
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.
Ortiz
Luis A
LA
Section of Pulmonary Diseases, Critical Care, and Environmental Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA. lortiz@tulane.edu
Champion
Hunter C
HC
Lasky
Joseph A
JA
Gambelli
Federica
F
Gozal
Evelyn
E
Hoyle
Gary W
GW
Beasley
Mary B
MB
Hyman
Albert L
AL
Friedman
Mitchell
M
Kadowitz
Philip J
PJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001761:Bleomycin; D001835:Body Weight / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D024042:Collagen Type I; D016328:NF-kappa B; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D004656:Enalapril