PMID- 34718575
OWN - NLM
STAT- MEDLINE
DCOM- 20220406
LR  - 20221029
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 31
IP  - 7
DP  - 2022 Mar 31
TI  - Heterozygous Tropomodulin 3 mice have improved lung vascularization after chronic 
      hypoxia.
PG  - 1130-1140
LID - 10.1093/hmg/ddab291 [doi]
AB  - The molecular mechanisms leading to high-altitude pulmonary hypertension (HAPH) 
      remains poorly understood. We previously analyzed the whole genome sequence of 
      Kyrgyz highland population and identified eight genomic intervals having a 
      potential role in HAPH. Tropomodulin 3 gene (TMOD3), which encodes a protein that 
      binds and caps the pointed ends of actin filaments and inhibits cell migration, 
      was one of the top candidates. Here we systematically sought additional evidence 
      to validate the functional role of TMOD3. In-silico analysis reveals that some of 
      the SNPs in HAPH associated genomic intervals were positioned in a regulatory 
      region that could result in alternative splicing of TMOD3. In order to 
      functionally validate the role of TMOD3 in HAPH, we exposed Tmod3-/+ mice to 
      4 weeks of constant hypoxia, i.e. 10% O2 and analyzed both functional 
      (hemodynamic measurements) and structural (angiography) parameters related to 
      HAPH. The hemodynamic measurements, such as right ventricular systolic pressure, 
      a surrogate measure for pulmonary arterial systolic pressure, and right 
      ventricular contractility (RV- +/- dP/dt), increases with hypoxia did not separate 
      between Tmod3-/+ and control mice. Remarkably, there was a significant increase 
      in the number of lung vascular branches and total length of pulmonary vascular 
      branches (P < 0.001) in Tmod3-/+ after 4 weeks of constant hypoxia as compared 
      with controls. Notably, the Tmod3-/+ endothelial cells migration was also 
      significantly higher than that from the wild-type littermates. Our results 
      indicate that, under chronic hypoxia, lower levels of Tmod3 play an important 
      role in the maintenance or neo-vascularization of pulmonary arteries.
CI  - (c) The Author(s) 2021. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Stobdan, Tsering
AU  - Stobdan T
AUID- ORCID: 0000-0002-2418-5156
AD  - Division of Respiratory Medicine, Department of Pediatrics, University of 
      California San Diego, La Jolla, CA 92093, USA.
FAU - Jain, Pritesh P
AU  - Jain PP
AD  - Department of Medicine, University of California San Diego, La Jolla, CA 92093, 
      USA.
FAU - Xiong, Mingmei
AU  - Xiong M
AD  - Department of Medicine, University of California San Diego, La Jolla, CA 92093, 
      USA.
FAU - Bafna, Vineet
AU  - Bafna V
AD  - Department of Computer Science & Engineering, University of California San Diego, 
      La Jolla, CA 92093, USA.
FAU - Yuan, Jason X-J
AU  - Yuan JX
AD  - Department of Medicine, University of California San Diego, La Jolla, CA 92093, 
      USA.
FAU - Haddad, Gabriel G
AU  - Haddad GG
AD  - Division of Respiratory Medicine, Department of Pediatrics, University of 
      California San Diego, La Jolla, CA 92093, USA.
AD  - Department of Neurosciences, University of California San Diego, La Jolla, CA 
      92093, USA.
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
LA  - eng
GR  - R01 GM114362/GM/NIGMS NIH HHS/United States
GR  - R01HL127403/NH/NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Tmod3 protein, mouse)
RN  - 0 (Tropomodulin)
SB  - IM
MH  - Actin Cytoskeleton/metabolism
MH  - Animals
MH  - *Endothelial Cells/metabolism
MH  - Hypoxia/genetics/metabolism
MH  - Lung/metabolism
MH  - Mice
MH  - Tropomodulin/chemistry/genetics/*metabolism
PMC - PMC8976430
EDAT- 2021/11/01 06:00
MHDA- 2022/04/07 06:00
PMCR- 2022/10/28
CRDT- 2021/10/31 21:05
PHST- 2021/05/03 00:00 [received]
PHST- 2021/09/13 00:00 [revised]
PHST- 2021/09/28 00:00 [accepted]
PHST- 2021/11/01 06:00 [pubmed]
PHST- 2022/04/07 06:00 [medline]
PHST- 2021/10/31 21:05 [entrez]
PHST- 2022/10/28 00:00 [pmc-release]
AID - 6413578 [pii]
AID - ddab291 [pii]
AID - 10.1093/hmg/ddab291 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2022 Mar 31;31(7):1130-1140. doi: 10.1093/hmg/ddab291.