Rapamycin Inhibits Smooth Muscle Cell Proliferation and Obstructive Arteriopathy Attributable to Elastin Deficiency.
Li, Wei; Li, Qingle; Qin, Lingfeng; Ali, Rahmat; Qyang, Yibing; Tassabehji, May; Pober, Barbara R.; Sessa, William C.; Giordano, Frank J.; Tellides, George
Arteriosclerosis, Thrombosis & Vascular Biology.
33(5):1028-1035, May 2013.
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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.
(C) 2013 American Heart Association, Inc.