PMID- 38081369
OWN - NLM
STAT- MEDLINE
DCOM- 20240129
LR  - 20240402
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 220
DP  - 2024 Feb
TI  - Unlocking the protective potential of the angiotensin type 2 receptor (AT(2)R) in 
      acute lung injury and age-related pulmonary dysfunction.
PG  - 115978
LID - S0006-2952(23)00571-3 [pii]
LID - 10.1016/j.bcp.2023.115978 [doi]
AB  - Despite its known importance in the cardiovascular system, the specific role and 
      impact of the angiotensin type 2 receptor (AT(2)R) in lung physiology and 
      pathophysiology remain largely elusive. In this study, we highlight the distinct 
      and specialized lung-specific roles of AT(2)R, primarily localized to an alveolar 
      fibroblast subpopulation, in contrast to the angiotensin type 1 receptor 
      (AT(1)R), which is almost exclusively expressed in lung pericytes. Evidence from 
      our research demonstrates that the disruption of AT(2)R (AT(2)R(-/y)), is 
      associated with a surge in oxidative stress and impaired lung permeability, which 
      were further intensified by Hyperoxic Acute Lung Injury (HALI). With aging, 
      AT(2)R(-/y) mice show an increase in oxidative stress, premature enlargement of 
      airspaces, as well as increased mortality when exposed to hyperoxia as compared 
      to age-matched WT mice. Our investigation into Losartan, an AT(1)R blocker, 
      suggests that its primary HALI lung-protective effects are channeled through 
      AT(2)R, as its protective benefits are absent in AT(2)R(-/y) mice. Importantly, a 
      non-peptide AT(2)R agonist, Compound 21 (C21), successfully reverses lung 
      oxidative stress and TGFbeta activation in wild-type (WT) mice exposed to HALI. 
      These findings suggest a possible paradigm shift in the therapeutic approach for 
      lung injury and age-associated pulmonary dysfunction, from targeting AT(1)R with 
      angiotensin receptor blockers (ARBs) towards boosting the protective function of 
      AT(2)R.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Abadir, Peter
AU  - Abadir P
AD  - Johns Hopkins University, Division of Geriatrics Medicine and Gerontology, 
      Department of Medicine, USA. Electronic address: Pabadir1@jhmi.edu.
FAU - Cosarderelioglu, Caglar
AU  - Cosarderelioglu C
AD  - Johns Hopkins University, Division of Geriatrics Medicine and Gerontology, 
      Department of Medicine, USA.
FAU - Damarla, Mahendra
AU  - Damarla M
AD  - Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, USA.
FAU - Malinina, Alla
AU  - Malinina A
AD  - Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, USA.
FAU - Dikeman, Dustin
AU  - Dikeman D
AD  - Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, USA.
FAU - Marx, Ruth
AU  - Marx R
AD  - Johns Hopkins University, Division of Geriatrics Medicine and Gerontology, 
      Department of Medicine, USA.
FAU - Nader, Monica M
AU  - Nader MM
AD  - Johns Hopkins University, Division of Geriatrics Medicine and Gerontology, 
      Department of Medicine, USA; Urbana High School, USA.
FAU - Abadir, Michael
AU  - Abadir M
AD  - University of Maryland College Park, USA.
FAU - Walston, Jeremy
AU  - Walston J
AD  - Johns Hopkins University, Division of Geriatrics Medicine and Gerontology, 
      Department of Medicine, USA.
FAU - Neptune, Enid
AU  - Neptune E
AD  - Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, USA. 
      Electronic address: Eneptune@jhmi.edu.
LA  - eng
GR  - P30 AG021334/AG/NIA NIH HHS/United States
GR  - R01 AG046441/AG/NIA NIH HHS/United States
GR  - R01 HL154343/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20231209
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Receptor, Angiotensin, Type 2)
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Angiotensin Receptor Antagonists)
RN  - 0 (Angiotensin-Converting Enzyme Inhibitors)
RN  - 0 (Receptor, Angiotensin, Type 1)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Receptor, Angiotensin, Type 2/genetics/agonists
MH  - Angiotensin II Type 1 Receptor Blockers/pharmacology/therapeutic use
MH  - Angiotensin Receptor Antagonists
MH  - Angiotensin-Converting Enzyme Inhibitors
MH  - Receptor, Angiotensin, Type 1/genetics
MH  - *Acute Lung Injury/drug therapy/prevention & control
PMC - PMC10880333
MID - NIHMS1954583
OTO - NOTNLM
OT  - Acute lung injury
OT  - Angiotensin type 2 receptor
OT  - Hyperoxic acute lung injury
OT  - Lung RAS
OT  - Renin-angiotensin signaling system
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/12/12 00:42
MHDA- 2024/01/29 06:44
PMCR- 2025/02/01
CRDT- 2023/12/11 19:23
PHST- 2023/07/30 00:00 [received]
PHST- 2023/12/07 00:00 [revised]
PHST- 2023/12/08 00:00 [accepted]
PHST- 2025/02/01 00:00 [pmc-release]
PHST- 2024/01/29 06:44 [medline]
PHST- 2023/12/12 00:42 [pubmed]
PHST- 2023/12/11 19:23 [entrez]
AID - S0006-2952(23)00571-3 [pii]
AID - 10.1016/j.bcp.2023.115978 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2024 Feb;220:115978. doi: 10.1016/j.bcp.2023.115978. Epub 2023 
      Dec 9.