PMID- 23493289
OWN - NLM
STAT- MEDLINE
DCOM- 20130612
LR  - 20211203
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Linking)
VI  - 33
IP  - 5
DP  - 2013 May
TI  - Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy 
      attributable to elastin deficiency.
PG  - 1028-35
LID - 10.1161/ATVBAHA.112.300407 [doi]
AB  - OBJECTIVE: Patients with elastin deficiency attributable to gene mutation 
      (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) 
      are characterized by obstructive arteriopathy resulting from excessive smooth 
      muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We 
      investigated whether rapamycin, an inhibitor of the cell growth regulator 
      mammalian target of rapamycin (mTOR) and effective against other SMC 
      proliferative disorders, is of therapeutic benefit in experimental models of 
      elastin deficiency. APPROACH AND RESULTS: As previously reported, Eln(-/-) mice 
      demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) 
      mice exhibited a smaller diameter aorta with more numerous but thinner elastic 
      lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of 
      newborn pups that was inhibited by maternal administration of rapamycin. mTOR 
      inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and 
      prevented medial hyperlamellation in Eln(+/-) weanlings without compromising 
      aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, 
      and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In 
      cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced 
      proliferation of SMC derived from patients with supravalvular aortic stenosis and 
      with Williams syndrome. CONCLUSIONS: mTOR inhibition may represent a 
      pharmacological strategy to treat diffuse arteriopathy resulting from elastin 
      deficiency.
FAU - Li, Wei
AU  - Li W
AD  - Department of Surgery, Interdepartmental Program in Vascular Biology and 
      Therapeutics, Yale University School of Medicine, New Haven, CT, USA.
FAU - Li, Qingle
AU  - Li Q
FAU - Qin, Lingfeng
AU  - Qin L
FAU - Ali, Rahmat
AU  - Ali R
FAU - Qyang, Yibing
AU  - Qyang Y
FAU - Tassabehji, May
AU  - Tassabehji M
FAU - Pober, Barbara R
AU  - Pober BR
FAU - Sessa, William C
AU  - Sessa WC
FAU - Giordano, Frank J
AU  - Giordano FJ
FAU - Tellides, George
AU  - Tellides G
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130314
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 9007-58-3 (Elastin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Aortic Stenosis, Supravalvular/complications
MH  - Arterial Occlusive Diseases/*etiology/prevention & control
MH  - Cell Proliferation/drug effects
MH  - Elastin/*deficiency
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Middle Aged
MH  - Muscle, Smooth, Vascular/cytology/*drug effects
MH  - Myocytes, Smooth Muscle/*drug effects/physiology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/physiology
MH  - Williams Syndrome/complications
EDAT- 2013/03/16 06:00
MHDA- 2013/06/13 06:00
CRDT- 2013/03/16 06:00
PHST- 2013/03/16 06:00 [entrez]
PHST- 2013/03/16 06:00 [pubmed]
PHST- 2013/06/13 06:00 [medline]
AID - ATVBAHA.112.300407 [pii]
AID - 10.1161/ATVBAHA.112.300407 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2013 May;33(5):1028-35. doi: 
      10.1161/ATVBAHA.112.300407. Epub 2013 Mar 14.