Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome.
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ABSTRACT:
SUBMITTER: Habashi JP
PROVIDER: S-EPMC8285055 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-beta (TGF-beta) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.
| S-EPMC1482474 | biostudies-literature
Project description:BackgroundAccording to previous studies, aortic diameter alone seems to be insufficient to predict the event of aortic dissection in Marfan syndrome (MFS). Determining the optimal schedule for preventive aortic root replacement (ARR) aortic growth rate is of importance, as well as family history, however, none of them appear to be decisive. Thus, the aim of this study was to search for potential predictors of aortic dissection in MFS.MethodsA Marfan Biobank consisting of 79 MFS patients was established. Thirty-nine MFS patients who underwent ARR were assigned into three groups based on the indication for surgery (dissection, annuloaortic ectasia and prophylactic surgery). The prophylactic surgery group was excluded from the study. Transforming growth factor-? (TGF-?) serum levels were measured by ELISA, relative expression of c-Fos, matrix metalloproteinase 3 and 9 (MMP-3 and -9) were assessed by RT-PCR. Clinical parameters, including anthropometric variables - based on the original Ghent criteria were also analyzed.ResultsAmong patients with aortic dissection, TGF-? serum level was elevated (43.78 ± 6.51 vs. 31.64 ± 4.99 ng/l, p < 0.0001), MMP-3 was up-regulated (Ln2? = 1.87, p = 0.062) and striae atrophicae were more common (92% vs. 41% p = 0.027) compared to the annuloaortic ectasia group.ConclusionsWe found three easily measurable parameters (striae atrophicae, TGF-? serum level, MMP-3) that may help to predict the risk of aortic dissection in MFS. Based on these findings a new classification of MFS, that is benign or malignant is also proposed, which could be taken into consideration in determining the timing of prophylactic ARR.
| S-EPMC4021409 | biostudies-literature
Project description:Background: Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown.Objectives: In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17?-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts.Results: Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17?-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells.Conclusions: Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.
| S-EPMC5510874 | biostudies-literature
Project description:A 17-year-old boy with a recent diagnosis of COVID-19 infection was admitted with acute chest pain due to type A aortic dissection and was subsequently diagnosed with the Marfan syndrome. Literature shows an increased rate of aortic dissection during flu season. The hypothesis is that a cytokine storm triggers the dissection.
| S-EPMC8682858 | biostudies-literature
Project description:In Marfan syndrome (MFS), dilation, dissection, and rupture of the aorta occur. Inflammation can be involved in the pathogenicity of aortic defects and can thus be a therapeutic target for MFS. Previously, we showed that the formulation of methotrexate (MTX) associated with lipid nanoparticles (LDE) has potent anti-inflammatory effects without toxicity. To investigate whether LDEMTX treatment can prevent the development of aortic lesions in the MFS murine model. MgΔloxPneo MFS (n = 40) and wild-type (WT, n = 60) mice were allocated to 6 groups weekly injected with IP solutions of: (1) only LDE; (2) commercial MTX; (3) LDEMTX (dose = 1mg/kg) between 3rd and 6th months of life. After 12 weeks of treatments, animals were examined by echocardiography and euthanatized for morphometric and molecular studies. MFS mice treated with LDEMTX showed narrower lumens in the aortic arch, as well as in the ascending and descending aorta. LDEMTX reduced fibrosis and the number of dissections in MFS but not the number of elastic fiber disruptions. In MFS mice, LDEMTX treatment lowered protein expression of pro-inflammatory factors macrophages (CD68), T-lymphocytes (CD3), tumor necrosis factor-α (TNF-α), apoptotic factor cleaved-caspase 3, and type 1 collagen and lowered the protein expression of the transforming growth factor-β (TGF-β), extracellular signal-regulated kinases ½ (ERK1/2), and SMAD3. Protein expression of CD68 and CD3 had a positive correlation with an area of aortic lumen (r 2 = 0.36; p < 0.001), suggesting the importance of inflammation in the causative mechanisms of aortic dilation. Enhanced adenosine availability by LDEMTX was suggested by higher aortic expression of an anti-adenosine A2a receptor (A2a) and lower adenosine deaminase expression. Commercial MTX had negligible effects. LDEMTX prevented the development of MFS-associated aortic defects and can thus be a candidate for testing in clinical studies.
| S-EPMC9226570 | biostudies-literature
Project description:Marfan syndrome (MFS) is a multi-system connective tissue disorder that results from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Although elastic fibers are compromised throughout the arterial tree, the most severe phenotype manifests in the ascending aorta. By comparing biaxial mechanics of the ascending and descending thoracic aorta in a mouse model of MFS, we show that aneurysmal propensity correlates well with both a marked increase in circumferential material stiffness and an increase in intramural shear stress despite a near maintenance of circumferential stress. This finding is corroborated via a comparison of the present results with previously reported findings for both the carotid artery from the same mouse model of MFS and for the thoracic aorta from another model of elastin-associated glycoprotein deficiency that does not predispose to thoracic aortic aneurysms. We submit that the unique biaxial loading of the ascending thoracic aorta conspires with fibrillin-1 deficiency to render this aortic segment vulnerable to aneurysm and rupture.
| S-EPMC4917480 | biostudies-literature
Project description:BackgroundMarfan syndrome (MFS) is an inherited connective tissue disease that mainly involves Fibrillin-1 (FBN1) mutations and aortic manifestations. In this study, we investigated the correlations between the FBN1 genotype-phenotype and aortic events (aortic dissection and aortic aneurysm) in patients with Marfan syndrome.MethodsGenotype and phenotype information was evaluated in 180 patients with MFS. DNA sequencing was performed on each patient. According to the clinical manifestation, these patients were split into two groups: the aortic dissection group and the aortic aneurysm group. Aortic wall tissue was obtained from Marfan patients who underwent surgery and was used for staining.ResultsA total of 180 patients with FBN1 mutations were grouped into four categories: 90 with missense mutations, 32 with splicing mutations, 29 with frameshift mutations, and 29 with nonsense mutations. There was a significantly higher frequency of frameshift and nonsense mutations observed in aortic dissection than in aortic aneurysm (25.58% vs. 4.35%, p = .005; 25.58% vs. 8.70%, p = .033, respectively;), while missense mutations showed a higher frequency in aortic aneurysm than in aortic dissection (69.57% vs. 32.56%, respectively; p < .001) and a higher rate of lens dislocation (34.78% vs. 13.95%, respectively; p = .008). Pathological staining showed that elastic fibers were sparser in patients with a frameshift and nonsense mutations, and the smooth muscle cells were sparser and more disorganized than those observed in patients with missense mutations.ConclusionThis study showed that FBN1 gene frameshift and nonsense mutations are more common in patients with aortic dissection and may have meaningful guidance for the treatment of Marfan syndrome patients.
| S-EPMC6978253 | biostudies-literature
Project description:Background Marfan syndrome (MFS) is a genetically transmitted connective tissue disorder characterized by aortic root dilatation, dissection, and rupture. Molecularly, MFS pathological features have been shown to be driven by increased angiotensin II in the aortic wall. Using an angiotensin II-driven aneurysm mouse model, we have recently demonstrated that local inhibition of leptin activity restricts aneurysm formation in the ascending and abdominal aorta. As we observed de novo leptin synthesis in the ascending aortic aneurysm wall of patients with MFS, we hypothesized that local counteracting of leptin activity in MFS may also prevent aortic cardiovascular complications in this context. Methods and Results Fbn1C1039G/+ mice underwent periaortic application of low-dose leptin antagonist at the aortic root. Treatment abolished medial degeneration and prevented increase in aortic root diameter (P<0.001). High levels of leptin, transforming growth factor β1, Phosphorylated Small mothers against decapentaplegic 2, and angiotensin-converting enzyme 1 observed in saline-treated MFS mice were downregulated in leptin antagonist-treated animals (P<0.01, P<0.05, P<0.001, and P<0.001, respectively). Leptin and angiotensin-converting enzyme 1 expression levels in left ventricular cardiomyocytes were also decreased (P<0.001) and coincided with prevention of left ventricular hypertrophy and aortic and mitral valve leaflet thickening (P<0.01 and P<0.05, respectively) and systolic function preservation. Conclusions Local, periaortic application of leptin antagonist prevented aortic root dilatation and left ventricular valve remodeling, preserving left ventricular systolic function in an MFS mouse model. Our results suggest that local inhibition of leptin may constitute a novel, stand-alone approach to prevent MFS aortic root aneurysms and potentially other similar angiotensin II-driven aortic pathological features.
| S-EPMC7660857 | biostudies-literature
Project description:Marfan syndrome (MFS) is an autosomal dominant connective disease etiologically related with FBN-1 gene mutation. The altered microfibril protein structure result in characteristic cardiovascular abnormalities including aortic root dilatation, aortic root aneurysms, and aortic dissections. Aortic root aneurysms and subsequent dissection are the major causes of reduced life expectancy in MFS patients. Prophylactic aortic root replacement has improved the survival of patients with MFS. Elective root replacement carries very low mortality and morbidity. Emergency root replacement for dissection is accompanied with higher early mortality and late deaths/interventions. Both the techniques of aortic root replacement, total root replacement (TRR) with a prosthetic valved conduit, and valve-sparing root replacement (VSRR) yield excellent early and late results. Considering the low risk of prosthetic valve-related events, the improved long-term survival, and event-free survival, TRR continues to be a very effective surgical option. VSSR also seems to be a good option for the first 10 to 15 years following surgery in MFS patients. The choice of procedure depends upon available expertise, patients' choice, feasibility of anticoagulation, possibility of pregnancy, and lifestyle of the patient. Aortic root morphology and state of valve cusps also affect the decision making. In recent times, personalized external aortic root support (PEARS) with a macroporous mesh sleeve has also emerged as a promising alternative to aortic root replacement. All these patients need close monitoring for whole life after surgical intervention.
| S-EPMC7525511 | biostudies-literature
Project description:Aortic dissection (AD) is mainly caused by hypertension and Marfan syndrome. However, it is unclear whether the cellular components and functions are different between the two causes. A total of 11 aortic samples were collected for single-cell RNA analysis and 20 clusters were disclosed, including VSMCs, fibroblasts, endothelial cells, T cells, B cells, monocytes, macrophages, mast cells, and neutrophils components. There were differences in cell subclusters and function between hypertension and Marfan patients. The cells also had different differentiations. Cellchat identified cell ligand-receptor interactions that were associated with hypertension and Marfan-induced AD involving SMC, fibroblast, mo-macrophages, and T-cell subsets. This study revealed the heterogeneity of cellular components and gene changes in hypertension and Marfan-induced AD. Through functional analysis and the changes in intercellular communication, the possible mechanisms of different causes of AD were explained from a new perspective, so we can better understand the occurrence and development of diseases.
| S-EPMC9253298 | biostudies-literature