Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways.
Acute respiratory distress syndrome (ARDS) caused by severe sepsis remains a major challenge in intensive care medicine. ACE2 has been shown to protect against lung injury. However, the mechanisms of its protective effects on ARDS are largely unknown. Here, we report that ACE2 prevents LPS-induced ARDS by inhibiting MAPKs and NF-κB signaling pathway. Lentiviral packaged Ace2 cDNA or Ace2 shRNA was intratracheally administrated into the lungs of male SD rats. Two weeks after gene transfer, animals received LPS (7.5 mg/Kg) injection alone or in combination with Mas receptor antagonist A779 (10 μg/Kg) or ACE2 inhibitor MLN-4760 (1 mg/Kg) pretreatment. LPS-induced lung injury and inflammatory response were significantly prevented by ACE2 overexpression and deteriorated by Ace2 shRNA. A779 or MLN-4760 pretreatment abolished the protective effects of ACE2. Moreover, overexpression of ACE2 significantly reduced the Ang II/Ang-(1-7) ratio in BALF and up-regulated Mas mRNA expression in lung, which was reversed by A779. Importantly, the blockade of ACE2 on LPS-induced phosphorylation of ERK1/2, p38 and p50/p65 was also abolished by A779. Whereas, only the ERK1/2 inhibitor significantly attenuated lung injury in ACE2 overexpressing rats pretreated with A779. Our observation suggests that AEC2 attenuates LPS-induced ARDS via the Ang-(1-7)/Mas pathway by inhibiting ERK/NF-κB activation.
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Yingchuan
Y
Li
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Zhen
Z
Zeng
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Yongmei
Y
Cao
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Yujing
Y
Liu
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Feng
F
Ping
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Mengfan
M
Liang
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Ying
Y
Xue
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Caihua
C
Xi
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Ming
M
Zhou
Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Wei
W
Jiang
D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D007093:Imidazoles / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D007093:Imidazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine