Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes

Moran, Corey S.; Jose, Roby J.; Moxon, Joseph V.; Roomberg, Alicia; Norman, Paul; Rush, Catherine M.; Körner, Heinrich; Golledge, Jonathan

doi:10.1161/atvbaha.112.301006

Cited by 42 publications

(43 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The precise benefits of rapamycin in this setting require further definition, but may relate to effects on SMC cytoskeleton organization besides its antiproliferative properties (40). Inhibition of mTOR signaling in vascular cells represents what we believe is a novel therapeutic approach to preventing aortic disease, although additional work is required to exclude an immunosuppressive effect as the relevant mechanism (41,42). However, a concern against the use of cytostatic agents is that fibroblast hyperplasia and adventitial thickening contribute to vessel wall integrity and may prevent fatal transmural rupture.…”

Section: Discussionmentioning

confidence: 99%

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

View full text Add to dashboard Cite

TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…It was reported that AngII infusion increased inflammatory mature monocytes, which differentiate into M1 macrophage in the bloodstream. 42 Both EPA and DHA may have the potential to inhibit AAA development by reducing the number of inflammatory monocytes. We assessed the inhibitory effects of ω3-PUFAs on early changes in the aorta after 5 days of AngII infusion, as per Study Protocol 1.…”

Section: Discussionmentioning

confidence: 99%

Omega 3 Polyunsaturated Fatty Acids Suppress the Development of Aortic Aneurysms Through the Inhibition of Macrophage-Mediated Inflammation

Yoshihara

Shimada

Fujita

et al. 2015

Circ J

View full text Add to dashboard Cite

“…Furthermore, recent data suggest that everolimus, an mTOR inhibitor, attenuated M1 polarization in ApoE -/-BMDMs in vitro and AAA formation in vivo. [35] The choice of BMDM as an in vitro model for changes observed in the intact suprarenal aorta is complicated by a recent bone marrow transplant study in which donor marrow from cholesterol fed LDLR -/-…”

Section: Tlr4mentioning

confidence: 99%

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

Qin

Bagley

Sukhova

et al. 2015

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Abdominal Aortic Aneurysm (AAA) is a major cause of mortality and morbidity in men over 65 years of age. Male apolipoprotein E knockout (ApoE -/-) mice infused with angiotensin II (AngII) develop AAA. Although AngII stimulates both JAK/STAT and Tolllike receptor 4 (TLR4) signaling pathways, their involvement in AngII mediated AAA formation is unclear. Here we used the small molecule STAT3 inhibitor, S3I-201, the TLR4 inhibitor Eritoran and ApoE -/- TLR4-/-mice to evaluate the interaction between STAT3 and TLR4 signaling in AngII-induced AAA formation. ApoE -/-mice infused for 28 days with AngII developed AAAs and increased STAT3 activation and TLR4 expression. Moreover, AngII increased macrophage infiltration and the ratio of M1 (proinflammatory)/M2 (healing) macrophages in aneurysmal tissue as early as 7-10 days after AngII infusion. STAT3 inhibition with S3I-201 decreased the incidence and severity of AngII-induced AAA formation and decreased MMP activity and the ratio of M1/M2 macrophages. Furthermore, AngII-mediated AAA formation, MMP secretion, STAT3 phosphorylation and the ratio of M1/M2 macrophages were markedly decreased in ApoE -/-TLR4 -/-mice, and in Eritoran-treated ApoE -/-mice. TLR4 and pSTAT3 levels were also increased in human aneurysmal tissue. These data support a role of pSTAT3 in TLR4 dependent AAA formation and possible therapeutic roles for TLR4 and/or STAT3 inhibition in AAA.

show abstract

Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes

Cited by 42 publications

References 48 publications

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

Omega 3 Polyunsaturated Fatty Acids Suppress the Development of Aortic Aneurysms Through the Inhibition of Macrophage-Mediated Inflammation

Angiotensin II-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3

Contact Info

Product

Resources

About