Supplementary MaterialsS1 File: (PDF) pone

Supplementary MaterialsS1 File: (PDF) pone. mice. Introduction Aortic aneurysm (AA) refers to a dilatation of the aorta due to loss of elasticity and degenerative weakening of its wall. Continuous growth of the aorta results in rupture and is associated with a high mortality rate [1]. Analyses of AA in experimental animal models, including the CaCl2-induced mouse model and the AngII-induced knockout (KO) mouse model [2, 3], are important for understanding the pathogenesis of this disease MLN4924 (HCL Salt) and for developing effective drug treatments aimed at arresting aortic growth [4C7]. Osteoprotegerin (Opg, also referred to as TNFRSF11B), a member of the tumor necrosis factor (TNF) receptor superfamily, functions as a decoy receptor to regulate various factors across many biological processes [8]. For example, ITGA6 Opg has been shown to MLN4924 (HCL Salt) regulate bone metabolism through the Receptor activator of nuclear factor kappa-B ligand (Rankl) [9, 10] and apoptosis of malignancy cells through TNF-related apoptosis-inducing ligand (Trail). Given that vascular illnesses get excited about bone tissue pathologies [11 frequently, 12], and because Opg is normally portrayed MLN4924 (HCL Salt) in vascular even muscles cells (VSMCs) [13] and serum degrees of OPG are raised in coronary disease [14C17], there is excellent curiosity about the functions Opg may play in the vascular system. We recently reported that Opg takes on a preventive part in the development of abdominal AA (AAA) in the CaCl2-induced aneurysm model [18]. In KO mice, we found larger aneurysms with damage of the aortic medial coating, which experienced increased manifestation of matrix metalloproteinase (Mmp)-9 and Trail. The manifestation of Opg in aortic cells was also improved in response to aneurysm induction in wild-type mice. We concluded with this recent study that Opg prevents AAA formation through its antagonistic effect on Trail. However, another group reported that Opg can promote the development of aneurysms in the suprarenal aorta (SRA) in the AngII-induced KO mouse model [19]. The authors of that study attributed the lower incidence of aneurysms and rupture in mice to the down-regulation of proteolytic enzyme manifestation. The two reports discussed above suggest opposing results for aneurysm formation in and mice relative to mice, which was also previously observed MLN4924 (HCL Salt) in the CaCl2-induced AAA model [18]. Our results suggest that Opg deficiency may lead to fibrotic redesigning of the aorta, probably enhanced by Trail signaling, and is an important pathological event that tends to limit AngII-induced SRA dilatation and dissection in KO mice. Results Opg deficiency tends to limit AngII-induced aortic dissection and dilatation In order to confirm the phenotypic variations in the two aneurysm models resulting from deficiency, we crossed KO MLN4924 (HCL Salt) mice with KO mice to generate mice. The KO mice were then treated with AngII to promote aneurysm development in the suprarenal aorta (SRA) (S1A Fig in S1 File). Although Moran et al. reported a significantly smaller median maximum diameter of the SRA in mice compared to that in mice relative to and mice appeared to be somewhat smaller, and multiple hematomas were observed in the SRA of mice, 50% of SRAs were dilated and only a few experienced dissected. This suggests that Opg deficiency may have a preventive effect on AngII-induced aortic dilatation and dissection (43.75% in mice). Open in a separate windows Fig 1 Opg deficiency tends to suppress AngII-induced aortic aneurysms.(A) Aortas of AngII-infused mice were categorized into three groups based on diameter and the presence of visible hematoma (No Aneurysm, Aneurysm, and Dissection organizations). Scale bars show 1 mm. (B) External diameter of the SRA in AngII-infused (white, n = 16) mice. All measurements are proven as container plots and each dimension is proven being a white group (No Aneurysm), grey triangle (Aneurysm), or dark combination (Dissection). (C) The occurrence (%) of aortic aneurysms is normally proven for No Aneurysm (white), Aneurysm.