PMID- 23054079
OWN - NLM
STAT- MEDLINE
DCOM- 20131021
LR  - 20211021
IS  - 1573-675X (Electronic)
IS  - 1360-8185 (Print)
IS  - 1360-8185 (Linking)
VI  - 18
IP  - 1
DP  - 2013 Jan
TI  - In vivo knockdown of intersectin-1s alters endothelial cell phenotype and causes 
      microvascular remodeling in the mouse lungs.
PG  - 57-76
LID - 10.1007/s10495-012-0762-x [doi]
AB  - Intersectin-1s (ITSN-1s) is a general endocytic protein involved in regulating 
      lung vascular permeability and endothelial cells (ECs) survival, via 
      MEK/Erk1/2(MAPK) signaling. To investigate the in vivo effects of ITSN-1s 
      deficiency and the resulting ECs apoptosis on pulmonary vasculature and lung 
      homeostasis, we used an ITSN-1s knocked-down (KD(ITSN)) mouse generated by 
      repeated delivery of a specific siRNA targeting ITSN-1 gene (siRNA(ITSN)). 
      Biochemical and histological analyses as well as electron microscopy (EM) 
      revealed that acute KD(ITSN) [3-days (3d) post-siRNA(ITSN) treatment] inhibited 
      Erk1/2(MAPK) pro-survival signaling, causing significant ECs apoptosis and lung 
      injury; at 10d of KD(ITSN), caspase-3 activation was at peak, terminal 
      deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive ECs showed 
      3.4-fold increase, the mean linear intercept (MLI) showed 48 % augment and 
      pulmonary microvessel density as revealed by aquaporin-1 staining (AQP-1) 
      decreased by 30 %, all compared to controls; pulmonary function was altered. 
      Concomitantly, expression of several growth factors known to activate 
      Erk1/2(MAPK) and suppress Bad pro-apoptotic activity increased. KD(ITSN) altered 
      Smads activity, downstream of the transforming growth factor beta-receptor-1 
      (TbetaR1), as shown by subcellular fractionation and immunoblot analyses. Moreover, 
      24d post-siRNA(ITSN), surviving ECs became hyper-proliferative and 
      apoptotic-resistant against ITSN-1s deficiency, as demonstrated by EM imaging, 
      5-bromo-deoxyuridine (BrdU) incorporation and Bad-Ser(112/155) phosphorylation, 
      respectively, leading to increased microvessel density and repair of the injured 
      lungs, as well as matrix deposition. In sum, ECs endocytic dysfunction and 
      apoptotic death caused by KD(ITSN) contribute to the initial lung injury and 
      microvascular loss, followed by endothelial phenotypic changes and microvascular 
      remodeling in the remaining murine pulmonary microvascular bed.
FAU - Bardita, Cristina
AU  - Bardita C
AD  - Department of Pharmacology, Rush University, 1735 W. Harrison St., Chicago, IL 
      60612, USA.
FAU - Predescu, Dan
AU  - Predescu D
FAU - Justice, Matthew J
AU  - Justice MJ
FAU - Petrache, Irina
AU  - Petrache I
FAU - Predescu, Sanda
AU  - Predescu S
LA  - eng
GR  - R01 HL089462/HL/NHLBI NIH HHS/United States
GR  - R01 HL105772/HL/NHLBI NIH HHS/United States
GR  - R01HL089462/HL/NHLBI NIH HHS/United States
GR  - R01HL089462-02S1/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Apoptosis
JT  - Apoptosis : an international journal on programmed cell death
JID - 9712129
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (intersectin 1)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/*deficiency/genetics
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Capillary Permeability/*drug effects
MH  - Endothelial Cells/cytology/*drug effects
MH  - Gene Knockdown Techniques
MH  - Lung/*blood supply/pathology/physiology
MH  - Lung Injury/pathology
MH  - Mice
MH  - Phenotype
PMC - PMC3543613
EDAT- 2012/10/12 06:00
MHDA- 2013/10/22 06:00
PMCR- 2012/10/07
CRDT- 2012/10/12 06:00
PHST- 2012/10/12 06:00 [entrez]
PHST- 2012/10/12 06:00 [pubmed]
PHST- 2013/10/22 06:00 [medline]
PHST- 2012/10/07 00:00 [pmc-release]
AID - 762 [pii]
AID - 10.1007/s10495-012-0762-x [doi]
PST - ppublish
SO  - Apoptosis. 2013 Jan;18(1):57-76. doi: 10.1007/s10495-012-0762-x.