PMID- 22693641
OWN - NLM
STAT- MEDLINE
DCOM- 20121002
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 6
DP  - 2012
TI  - ACE2 deficiency enhances angiotensin II-mediated aortic profilin-1 expression, 
      inflammation and peroxynitrite production.
PG  - e38502
LID - 10.1371/journal.pone.0038502 [doi]
LID - e38502
AB  - Inflammation and oxidative stress play a crucial role in angiotensin (Ang) 
      II-mediated vascular injury. Angiotensin-converting enzyme 2 (ACE2) has recently 
      been identified as a specific Ang II-degrading enzyme but its role in vascular 
      biology remains elusive. We hypothesized that loss of ACE2 would facilitate Ang 
      II-mediated vascular inflammation and peroxynitrite production. 10-week wildtype 
      (WT, Ace2(+/y)) and ACE2 knockout (ACE2KO, Ace2(-/y)) mice received with 
      mini-osmotic pumps with Ang II (1.5 mg.kg(-)(1).d(-)(1)) or saline for 2 weeks. Aortic 
      ACE2 protein was obviously reduced in WT mice in response to Ang II related to 
      increases in profilin-1 protein and plasma levels of Ang II and Ang-(1-7). Loss 
      of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of 
      inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interleukin 
      (IL)-1beta, and IL-6 without affecting tumor necrosis factor-alpha in aortas of ACE2KO 
      mice. Furthermore, ACE2 deficiency led to greater increases in Ang II-mediated 
      profilin-1 expression, NADPH oxidase activity, and superoxide and peroxynitrite 
      production in the aortas of ACE2KO mice associated with enhanced phosphorylated 
      levels of Akt, p70S6 kinase, extracellular signal-regulated kinases (ERK1/2) and 
      endothelial nitric oxide synthase (eNOS). Interestingly, daily treatment with AT1 
      receptor blocker irbesartan (50 mg/kg) significantly prevented Ang II-mediated 
      aortic profilin-1 expression, inflammation, and peroxynitrite production in WT 
      mice with enhanced ACE2 levels and the suppression of the Akt-ERK-eNOS signaling 
      pathways. Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic 
      inflammation and peroxynitrite production associated with the augmentation of 
      profilin-1 expression and the activation of the Akt-ERK-eNOS signaling, 
      suggesting potential therapeutic approaches by enhancing ACE2 action for patients 
      with vascular diseases.
FAU - Jin, Hai-Yan
AU  - Jin HY
AD  - State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Song, Bei
AU  - Song B
FAU - Oudit, Gavin Y
AU  - Oudit GY
FAU - Davidge, Sandra T
AU  - Davidge ST
FAU - Yu, Hui-Min
AU  - Yu HM
FAU - Jiang, Yan-Yan
AU  - Jiang YY
FAU - Gao, Ping-Jin
AU  - Gao PJ
FAU - Zhu, Ding-Liang
AU  - Zhu DL
FAU - Ning, Guang
AU  - Ning G
FAU - Kassiri, Zamaneh
AU  - Kassiri Z
FAU - Penninger, Josef M
AU  - Penninger JM
FAU - Zhong, Jiu-Chang
AU  - Zhong JC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120605
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Profilins)
RN  - 104821-25-2 (dihydroethidium)
RN  - 11128-99-7 (Angiotensin II)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - 3604-79-3 (3-nitrotyrosine)
RN  - 42HK56048U (Tyrosine)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.4.15.1 (Peptidyl-Dipeptidase A)
RN  - EC 3.4.17.23 (Ace2 protein, mouse)
RN  - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
RN  - EN464416SI (Ethidium)
SB  - IM
MH  - Angiotensin II/*pharmacology
MH  - Angiotensin-Converting Enzyme 2
MH  - Animals
MH  - Aorta/*drug effects/*metabolism
MH  - Blotting, Western
MH  - Chemokine CCL2/metabolism
MH  - Ethidium/analogs & derivatives/metabolism
MH  - Inflammation/*metabolism
MH  - Interleukin-1beta/metabolism
MH  - Interleukin-6/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - NADPH Oxidases/metabolism
MH  - Peptidyl-Dipeptidase A/*deficiency/genetics
MH  - Peroxynitrous Acid/*metabolism
MH  - Profilins/genetics/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Tyrosine/analogs & derivatives/metabolism
PMC - PMC3367919
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/06/14 06:00
MHDA- 2012/10/04 06:00
PMCR- 2012/06/05
CRDT- 2012/06/14 06:00
PHST- 2012/03/03 00:00 [received]
PHST- 2012/05/10 00:00 [accepted]
PHST- 2012/06/14 06:00 [entrez]
PHST- 2012/06/14 06:00 [pubmed]
PHST- 2012/10/04 06:00 [medline]
PHST- 2012/06/05 00:00 [pmc-release]
AID - PONE-D-12-06408 [pii]
AID - 10.1371/journal.pone.0038502 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(6):e38502. doi: 10.1371/journal.pone.0038502. Epub 2012 Jun 5.