PMID- 28973855
OWN - NLM
STAT- MEDLINE
DCOM- 20180626
LR  - 20220409
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 41
DP  - 2017 Oct 10
TI  - Autophagy is required for endothelial cell alignment and atheroprotection under 
      physiological blood flow.
PG  - E8675-E8684
LID - 10.1073/pnas.1702223114 [doi]
AB  - It has been known for some time that atherosclerotic lesions preferentially 
      develop in areas exposed to low SS and are characterized by a proinflammatory, 
      apoptotic, and senescent endothelial phenotype. Conversely, areas exposed to high 
      SS are protected from plaque development, but the mechanisms have remained 
      elusive. Autophagy is a protective mechanism that allows recycling of defective 
      organelles and proteins to maintain cellular homeostasis. We aimed to understand 
      the role of endothelial autophagy in the atheroprotective effect of high SS. 
      Atheroprotective high SS stimulated endothelial autophagic flux in human and 
      murine arteries. On the contrary, endothelial cells exposed to atheroprone low SS 
      were characterized by inefficient autophagy as a result of mammalian target of 
      rapamycin (mTOR) activation, AMPKalpha inhibition, and blockade of the autophagic 
      flux. In hypercholesterolemic mice, deficiency in endothelial autophagy increased 
      plaque burden only in the atheroresistant areas exposed to high SS; plaque size 
      was unchanged in atheroprone areas, in which endothelial autophagy flux is 
      already blocked. In cultured cells and in transgenic mice, deficiency in 
      endothelial autophagy was characterized by defects in endothelial alignment with 
      flow direction, a hallmark of endothelial cell health. This effect was associated 
      with an increase in endothelial apoptosis and senescence in high-SS regions. 
      Deficiency in endothelial autophagy also increased TNF-alpha-induced inflammation 
      under high-SS conditions and decreased expression of the antiinflammatory factor 
      KLF-2. Altogether, these results show that adequate endothelial autophagic flux 
      under high SS limits atherosclerotic plaque formation by preventing endothelial 
      apoptosis, senescence, and inflammation.
FAU - Vion, Anne-Clemence
AU  - Vion AC
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Kheloufi, Marouane
AU  - Kheloufi M
AUID- ORCID: 0000-0002-2411-4497
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, 75013 Paris, France.
FAU - Hammoutene, Adel
AU  - Hammoutene A
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Poisson, Johanne
AU  - Poisson J
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Lasselin, Juliette
AU  - Lasselin J
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Devue, Cecile
AU  - Devue C
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Pic, Isabelle
AU  - Pic I
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Dupont, Nicolas
AU  - Dupont N
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - INSERM U1151, Institut Necker-Enfants Malades-INEM, 75014 Paris, France.
AD  - CNRS UMR 8253, 75014 Paris, France.
FAU - Busse, Johanna
AU  - Busse J
AD  - Medizinische Klinik I, Klinikum der Universitat Munchen, 81377 Munich, Germany.
FAU - Stark, Konstantin
AU  - Stark K
AD  - Medizinische Klinik I, Klinikum der Universitat Munchen, 81377 Munich, Germany.
FAU - Lafaurie-Janvore, Julie
AU  - Lafaurie-Janvore J
AD  - Mechanics & Living Systems, Cardiovascular Cellular Engineering, Laboratoire 
      d'Hydrodynamique, Ecole Polytechnique, UMR 7646, 91128 Palaiseau, France.
FAU - Barakat, Abdul I
AU  - Barakat AI
AD  - Mechanics & Living Systems, Cardiovascular Cellular Engineering, Laboratoire 
      d'Hydrodynamique, Ecole Polytechnique, UMR 7646, 91128 Palaiseau, France.
FAU - Loyer, Xavier
AU  - Loyer X
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Souyri, Michele
AU  - Souyri M
AD  - INSERM UMR_S1131/IHU/Universite Paris Diderot, 75013 Paris, France.
FAU - Viollet, Benoit
AU  - Viollet B
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - INSERM U1016, Institut Cochin, 75014 Paris, France.
AD  - CNRS, UMR 8104, 75014 Paris, France.
FAU - Julia, Pierre
AU  - Julia P
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - Service de Chirurgie Cardiaque et Vasculaire, Hopital Europeen Georges Pompidou, 
      AP-HP, 75015 Paris, France.
FAU - Tedgui, Alain
AU  - Tedgui A
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Codogno, Patrice
AU  - Codogno P
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - INSERM U1151, Institut Necker-Enfants Malades-INEM, 75014 Paris, France.
AD  - CNRS UMR 8253, 75014 Paris, France.
FAU - Boulanger, Chantal M
AU  - Boulanger CM
AUID- ORCID: 0000-0002-3687-651X
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France; 
      chantal.boulanger@inserm.fr.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
FAU - Rautou, Pierre-Emmanuel
AU  - Rautou PE
AD  - INSERM, U970, Paris Cardiovascular Research Center, 75015 Paris, France.
AD  - Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
AD  - Universite Paris Diderot, Sorbonne Paris Cite, 75013 Paris, France.
AD  - Departement Hospitalo-Universitaire Unity, Pole des Maladies de l'Appareil 
      Digestif, Service d'Hepatologie, Centre de Reference des Maladies Vasculaires du 
      Foie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, 92110 Clichy, 
      France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170925
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Atherosclerosis/metabolism/pathology/*prevention & control
MH  - *Autophagy
MH  - Cellular Senescence
MH  - Female
MH  - Human Umbilical Vein Endothelial Cells/*cytology/metabolism
MH  - Humans
MH  - Hypercholesterolemia/*physiopathology
MH  - Inflammation/metabolism/pathology/*prevention & control
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - *Stress, Physiological
PMC - PMC5642679
OTO - NOTNLM
OT  - atherosclerosis
OT  - autophagy
OT  - endothelial
OT  - inflammation
OT  - shear stress
COIS- The authors declare no conflict of interest.
EDAT- 2017/10/05 06:00
MHDA- 2018/06/27 06:00
PMCR- 2018/04/10
CRDT- 2017/10/05 06:00
PHST- 2017/10/05 06:00 [pubmed]
PHST- 2018/06/27 06:00 [medline]
PHST- 2017/10/05 06:00 [entrez]
PHST- 2018/04/10 00:00 [pmc-release]
AID - 1702223114 [pii]
AID - 201702223 [pii]
AID - 10.1073/pnas.1702223114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8675-E8684. doi: 
      10.1073/pnas.1702223114. Epub 2017 Sep 25.