Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice.
Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha-elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease.
Cao
Jiumei
J
Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Gong
Limin
L
Guo
Dong-chuan
DC
Mietzsch
Ulrike
U
Kuang
Shao-Qing
SQ
Kwartler
Callie S
CS
Safi
Hazim
H
Estrera
Anthony
A
Gambello
Michael J
MJ
Milewicz
Dianna M
DM
D000818:Animals; D001013:Aorta, Thoracic / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001014:Aortic Aneurysm / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D003285:Contractile Proteins / Q000378:metabolism; D004549:Elastin / Q000494:pharmacology; D006801:Humans; D018810:Magnetic Resonance Angiography; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009154:Mutation / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D011506:Proteins; D011859:Radiography; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013896:Thoracic Diseases / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D014157:Transcription Factors / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D003285:Contractile Proteins; D046912:Multiprotein Complexes; D010455:Peptides; D011506:Proteins; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004549:Elastin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins