In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
Abstract:
Aortic aneurysms represent a life-threatening condition because of the current lack of effective treatment, with therapeutic options limited to emergency surgery. Aneurysm formation is typically associated with extracellular matrix remodeling and persistent inflammation. Although the molecular mechanisms underlying aortic pathology remain largely unclear, TGFβ signaling is unquestionably implied and its downstream target Smad4 showed protective functions for maintenance of aortic walls’ integrity. Using mice with smooth muscle cells (SMCs) specific deletion of Smad4 in the adult ( Smad4 -SMC iko ), developing spontaneous aneurysms, we investigated the molecular mechanisms activated by dysregulation of TGFβ signaling. Structural disarrangement of ascending aorta media in Smad4 -SMC iko mice was clearly appreciated early after Smad4 deletion as discrete breaks of elastic lamellae. Interestingly, the islands of damage evidenced in the aorta of Smad4 -SMC iko were enriched of immune infiltrate, mainly composed by monocytes/macrophages, as indicated by flow cytometry and immunofluorescence. We then analyzed several pathways downstream to Smad4 inhibition, finding a selective activation of NF-kB/IL-1β pathway in SMCs. This danger signal released by SMCs later recruits innate immunity, hence arising inflammation. In order to test the relevance of this pathway in the formation of aneurysms induced by TGFβ dysregulation, we deleted Smad4 in SMCs of mice with Il1r1 null background ( Smad4 -SMC iko ; Il1r1 -/- ). Serial ultrasonographic analyses revealed that ablation of IL1 receptor 1 protected mice with the SMCs deletion of Smad4 from the progression of pathology and improved their overall survival. In the end, to test the translational potential of our findings, we neutralized IL-1β signaling with the clinically relevant murine version of the FDA-approved clinical drug canakinumab. During a time course of 16 weeks, while a weekly administration of control immunoglobulins did not change aneurysm progression in Smad4 -SMC iko mice, treatment with anti-IL-1β antibody significantly hampered aneurysm formation in the aorta. These findings identify a mechanistic target for controlling aneurysms progression induced by disrupted TGFβ signaling.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.37.suppl_1.300
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1494427-3
