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Proteomics reveals Rictor as a noncanonical TGF-? signaling target during aneurysm progression in Marfan mice.

ABSTRACT: The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1^C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-?-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr¹¹³⁵ in a separate cohort of mice and showed in vitro that TGF-? activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of ?₃-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that ?₃-integrin expression and activation modulated TGF-?-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-? signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by ?₃-integrin constitute a modulator of transforming growth factor-?-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.

SUBMITTER: Parker SJ

PROVIDER: S-EPMC6335018 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice.

Parker Sarah J SJ Stotland Aleksandr A MacFarlane Elena E Wilson Nicole N Orosco Amanda A Venkatraman Vidya V Madrid Kyle K Gottlieb Roberta R Dietz Harry C HC Van Eyk Jennifer E JE

American journal of physiology. Heart and circulatory physiology 20180713 5

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1<sup>C1041G/+</sup>) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-β-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingen ...[more]

PMID: 30004239

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Project description:Background Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced Erk (extracellular-signal-regulated kinase)/Smad activation, contributing to aneurysm progression in males. Methods and Results Aortic diameters in Fbn1C1039G/+ and littermate wild-type controls were measured at ages 6, 8, 12, and 16 weeks. Fbn1C1039G/+ males were treated with (1) flutamide (androgen receptor blocker) or (2) vehicle control from age 6 to 16 weeks and then euthanized. p-Erk1/2, p-Smad2, and matrix metalloproteinase (MMP) activity were measured in ascending/aortic root and descending aorta specimens. Fbn1C1039G/+ male and female ascending/aortic root-derived smooth muscle cells were utilized in vitro to measure Erk/Smad activation and MMP-2 activity following dihydrotestosterone, flutamide or transforming growth factor beta 1 treatment. Fbn1C1039G/+ males have increased aneurysm growth. p-Erk1/2 and p-Smad2 were elevated in ascending/aortic root specimens at age 16 weeks. Corresponding with enhanced Erk/Smad signaling, MMP-2 activity was higher in Fbn1C1039G/+ males. In vitro smooth muscle cell studies revealed that dihydrotestosterone potentiates transforming growth factor beta-induced Erk/Smad activation and MMP-2 activity, which is reversed by flutamide treatment. Finally, in vivo flutamide treatment reduced aneurysm growth via p-Erk1/2 and p-Smad2 reduction in Fbn1C1039G/+ males. Conclusions Fbn1C1039G/+ males have enhanced aneurysm growth compared with females associated with enhanced p-Erk1/2 and p-Smad2 activation. Mechanistically, in vitro smooth muscle cell studies suggested that dihydrotestosterone potentiates transforming growth factor beta induced Erk/Smad activation. As biological proof of concept, flutamide treatment attenuated aneurysm growth and p-Erk1/2 and p-Smad2 signaling in Fbn1C1039G/+ males.

Dataset Information

Proteomics reveals Rictor as a noncanonical TGF-? signaling target during aneurysm progression in Marfan mice.

Publications

Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice.

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