Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency.

Abstract

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.

• Authors: Wei Li, Qingle Li, Lingfeng Qin, Rahmat Ali, Yibing Qyang, May Tassabehji, Barbara R Pober, William C Sessa, Frank J Giordano, George Tellides
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 5 Pg. 1028-35 (May 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23493289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Elastin
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adult
• Animals
• Aortic Stenosis, Supravalvular (complications)
• Arterial Occlusive Diseases (etiology, prevention & control)
• Cell Proliferation (drug effects)
• Elastin (deficiency)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Muscle, Smooth, Vascular (cytology, drug effects)
• Myocytes, Smooth Muscle (drug effects, physiology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Williams Syndrome (complications)