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. and rapamycin reduces the incidence of intimal thickening in coronary arteries of rejecting cardiac allografts. Conclusions-mTOR11 The therapeutic benefit of mTOR inhibitors in arteriosclerosis is ascribed to their potent antimitogenic effect.12,13 We hypothesized that inhibition of SMC proliferation by rapamycin will also prevent obstructive arteriopathy mediated by elastin deficiency, and we tested this strategy in experimental systems of SVAS and WS.14,15 Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Murine Models of Elastin-Deficient AortopathyTo investigate pathogenetic mechanisms and therapeutic opportunities in SVAS and WS, we used an established murine model in which a targeted mutation of exon 1 disrupts the Eln allele. 4 As previously reported, 4-6 pups homozygous for loss of Eln died by 3 days of birth with severe stenosis of the thoracic aorta sparing its root ( Figure 1A), whereas heterozygote animals survived long term characterized by modestly decreased aortic diameter ( Figure 1B) with an increased number of medial elastic lamellae ( Figure 1C). Ultrastructural analysis of aortas from adult Eln haploinsufficient mice showed the elastic laminae to be thinner structures, whereas SMC morphology seemed normal ( Figure I in the online-only Data Supplement). Thus, newborn and mature animals offer different arteriopathy end points to assess depending on gene dosage. Increased mTOR Signaling in ElastinDeficient Aortas Is Inhibited by RapamycinWe examined for dysregulation of mTOR signaling, because this pathway plays a crucial role in SMC proliferation in other obstr...

Curcumin Attenuates Rapamycin-induced Cell Injury of Vascular Endothelial Cells

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Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

“…The role of SMC proliferation was further investigated using a pharmacological inhibitor of mTOR signaling. Rapamycin administered at 2 mg/kg/d, a validated therapeutic dose in other models of arterial disease characterized by SMC hyperplasia (34,35), resulted in whole-blood trough levels of 27.3 ± 5.0 ng/ml (n = 6). This treatment strategy inhibited mTOR and ERK1/2 signaling of KO aorta in vivo ( Figure 5G).…”

Overnutrition, mTOR signaling, and cardiovascular diseases

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