scholarly journals Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Maria C. Guido ◽  
Victor Debbas ◽  
Vera M. Salemi ◽  
Elaine R. Tavares ◽  
Thayna Meirelles ◽  
...  
Keyword(s):  
Mouse Model ◽  
Marfan Syndrome ◽  
Lipoic Acid ◽  
Elastic Fiber ◽  
Aortic Aneurysms ◽  
Ros Generation ◽  
Ros Production ◽  
Aortic Dilation ◽  
Advanced Stages ◽  
Aortic Remodeling

Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgΔloxPneo mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture.

scholarly journals 2464 Sexual dimorphism in a mouse model of syndromic thoracic aortic aneurysm

2018 ◽  
Vol 2 (S1) ◽  
pp. 27-27
Author(s):  
Zheying Chen ◽  
Alan Daugherty ◽  
Mary Sheppard
Keyword(s):  
Extracellular Matrix ◽  
Sexual Dimorphism ◽  
Mouse Model ◽  
Aortic Aneurysms ◽  
Pcr Analysis ◽  
Wild Type ◽  
Aortic Dilation ◽  
Male And Female ◽  
Thoracic Aortic Aneurysms ◽  
Male Sex

OBJECTIVES/SPECIFIC AIMS: Pre-clinical and clinical observations have noted that increased aortic dilation is associated with male sex. Using an experimental model of severe, syndromic thoracic aortic aneurysms, we quantify aortic dilation and elastin stability in male Versus female mice. METHODS/STUDY POPULATION: Ascending aortas from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. At termination, aortas were harvested for RT-PCR analysis of extracellular matrix genes. Aortas were serially sectioned and elastin fragmentation was imaged by auto-fluorescence. RESULTS/ANTICIPATED RESULTS: At 12 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice were significantly different (2.24±0.43 vs. 1.57±0.22 mm; p=0.002), while there were no significant differences between sexes of wild type littermates (1.29±0.13 vs. 1.23±0.08 mm; p=0.71). Male sex was associated with increased elastin but not fibrillin-1 mRNA expression. Ascending aortas from male and female FBN1mgR/mgR mice significantly differed in the degree of elastin fragmentation (2.76 vs. 1.85 breaks/ 100 µm aorta; p=0.03). DISCUSSION/SIGNIFICANCE OF IMPACT: Sexual dimorphism of thoracic aortic dilation observed in human TAA patients was recapitulated in the fibirllin-1 hypomorphic mouse model of syndromic thoracic aortic aneurysms. Differences in this mouse model could be explained by the differential expression of extracellular matrix genes.

scholarly journals Inducible Prmt1 ablation in adult vascular smooth muscle leads to contractile dysfunction and aortic dissection

2021 ◽  
Author(s):  
Jung-Hoon Pyun ◽  
Byeong-Yun Ahn ◽  
Tuan Anh Vuong ◽  
Su Woo Kim ◽  
Yunju Jo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Dissection ◽  
Vascular Smooth Muscle ◽  
Vascular Function ◽  
Ex Vivo ◽  
Elastic Fiber ◽  
Aortic Aneurysms ◽  
Aortic Dilation ◽  
Smooth Muscle Contractility

AbstractVascular smooth muscle cells (VSMCs) have remarkable plasticity in response to diverse environmental cues. Although these cells are versatile, chronic stress can trigger VSMC dysfunction, which ultimately leads to vascular diseases such as aortic aneurysm and atherosclerosis. Protein arginine methyltransferase 1 (Prmt1) is a major enzyme catalyzing asymmetric arginine dimethylation of proteins that are sources of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Although a potential role of Prmt1 in vascular pathogenesis has been proposed, its role in vascular function has yet to be clarified. Here, we investigated the role and underlying mechanism of Prmt1 in vascular smooth muscle contractility and function. The expression of PRMT1 and contractile-related genes was significantly decreased in the aortas of elderly humans and patients with aortic aneurysms. Mice with VSMC-specific Prmt1 ablation (smKO) exhibited partial lethality, low blood pressure and aortic dilation. The Prmt1-ablated aortas showed aortic dissection with elastic fiber degeneration and cell death. Ex vivo and in vitro analyses indicated that Prmt1 ablation significantly decreased the contractility of the aorta and traction forces of VSMCs. Prmt1 ablation downregulated the expression of contractile genes such as myocardin while upregulating the expression of synthetic genes, thus causing the contractile to synthetic phenotypic switch of VSMCs. In addition, mechanistic studies demonstrated that Prmt1 directly regulates myocardin gene activation by modulating epigenetic histone modifications in the myocardin promoter region. Thus, our study demonstrates that VSMC Prmt1 is essential for vascular homeostasis and that its ablation causes aortic dilation/dissection through impaired myocardin expression.

Age and Sex Dependency of Thoracic Aortopathy in a Mouse Model of Marfan Syndrome

2021 ◽  
Author(s):  
Nazli Gharraee ◽  
Yujian Sun ◽  
Joseph A. Swisher ◽  
Susan M. Lessner
Keyword(s):  
Mouse Model ◽  
Marfan Syndrome ◽  
Aortic Wall ◽  
Second Harmonic ◽  
Severe Damage ◽  
Aortic Dilation ◽  
Second Harmonic Generation Microscopy ◽  
Percent Increase ◽  
Aneurysm Growth ◽  
Sex Dependency

Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of Marfan syndrome translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin1 C1041G/+ were used as a mouse model of MFS. Ultrasound measurements from 3-12 months showed increased aortic diameter in Marfan aorta with larger percent increase in diameter for males compared to females. Immunohistochemistry showed decreased contractile smooth muscle cells in Marfan aortic wall compared to healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second harmonic generation microscopy of collagen fibers and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female heterozygotes showed increased expression of Sca-1-positive adventitial progenitor cells vs. controls at young ages. In agreement with clinical data, Marfan mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth.

scholarly journals Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Circulation ◽  
2021 ◽  
Author(s):  
Jorge Oller ◽  
Enrique Gabandé-Rodríguez ◽  
María Jesús Ruiz-Rodriguez ◽  
Gabriela Desdín-Micó ◽  
Juan Francisco Aranda ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Mitochondrial Dysfunction ◽  
Marfan Syndrome ◽  
Mitochondrial Respiration ◽  
Thoracic Aortic Aneurysm ◽  
Lactate Production ◽  
Aortic Disease ◽  
Aortic Aneurysms

Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm (TAA). To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from a Marfan mouse model ( Fbn1 c1039g/+ ) and MFS-patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMCs) by conditional depleting mitochondrial transcription factor A (Tfam) ( Myh11-Cre ERT2 Tfam flox/flox mice). We have used a mouse model of Marfan syndrome to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1 c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial-DNA content, were reduced in aortas from young Fbn1 c1039g/+ mice. In vitro experiments in Fbn1 -silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS-patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient-VSMCs mice, lose their contractile capacity, showed aortic aneurysms and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside (NR) rapidly reverses aortic aneurysm in Fbn1 c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan Syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

scholarly journals TLR4 Inhibitor Alleviates Sepsis-Induced Organ Failure by Inhibiting Platelet Mtros Production, Autophagy, and Gpiib/Iiia Expression

2021 ◽  
Author(s):  
Ying Li ◽  
Guo Feng
Keyword(s):  
Mouse Model ◽  
Organ Failure ◽  
Platelet Activation ◽  
Organ Injury ◽  
Ros Generation ◽  
Pathophysiological Mechanism ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mitochondrial Ros

Abstract Thrombocytopenia and impaired platelet aggregation are associated with sepsis-induced organ failure. Many studies have shown that mitochondrial ROS, autophagy is related to organ injury in sepsis. However, the relationship between them is unknown. Here, we explored whether Toll Like Receptor 4 inhibitor alleviates sepsis organ failure by inhibiting platelet mitochondrial ROS production, autophagy, and GPIIb/IIIa expression. We found Toll Like Receptor 4 inhibitor TAK242 alleviated LPS-induced acute kidney and lung injury and decrease platelet activation in a mouse model of sepsis mice. In vitro study, inhibiting Toll Like Receptor 4 reduced inward flow of Ca2+ and decreased endogenous mitochondrial ROS production in platelets treated with LPS, and TAK242 inhibited autophagy and NOX expression in LPS treated platelets. Thus, we supposed that Toll Like Receptor 4 inhibitor effectively alleviate lung and kidney injury in a mouse model of sepsis induced by LPS and its effects are related to the inhibition of mouse platelets GPIIb/IIIa, and also can reduce LPS-induced mitochondrial ROS generation related to Ca2+ influx, thus reducing platelet activation. LPS can induce platelet autophagy by generating mitochondrial ROS, which may be the pathophysiological mechanism of organ injury in sepsis.

Abstract 255: Loss of Alk5 in Smooth Muscle Cells (SMCs) Causes Aortic Aneurysms Through an Aberrant Tgfbr2 Signal

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Pu Yang ◽  
Chunhua Fu ◽  
Michael Hong ◽  
Bradley Schmit ◽  
Kennyth DeSart ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Gene Deletion ◽  
Aortic Rupture ◽  
Elastic Fiber ◽  
Aortic Aneurysms ◽  
Aortic Dilation ◽  
Aneurysm Formation ◽  
Aortic Pathology ◽  
Primary Driver ◽  
Fiber Breaks

TGF-β signaling disorder has emerged as a cause for aortic aneurysm formation. However, mechanistic details of this disorder remain poorly defined. This study sought to understand the TGF-β signaling propagation and its impact on aortic structural homeostasis under conditions of receptor deficiency. An inducible gene deletion system driven by Myh11-CreER was utilized for selective removal of receptors Alk5, Tgfbr2, or both in SMCs, termed Alk5iko, Tgfbr2iko, and Alk5iko Tgfbr2iko, respectively. Alk5-floxed (Alk5f/f) mice served as controls. Animals (male, 9-11 weeks of age) were followed up to six months following gene deletion. Alk5iko caused progressive aortic enlargement (ultrasound scan). In four weeks, 23% of animals (n=42) died from aortic rupture, with the survivals all showing severe aneurysmal degeneration at locations of ascending (100%), descending (43%) and/or suprarenal (50%) aortas. Surprisingly, Tgfbr2iko in age-matched males (n=26) was well tolerated. Neither rupture nor aortic dilation was noted in four weeks. Evidence of aortic pathology was limited to scattered elastic fiber breaks. To evaluate the role of TGF-β in aortic aneurysm formation in Alk5iko animals, we deleted Tgfbr2 simultaneously with Alk5. The additional Tgfbr2iko completely recused aortic rupture, attenuated aortic dilation from 68% to 25%, and significantly improved aortic histology. Compared to the Alk5f/f controls, Alk5iko, Tgfbr2iko, and Alk5iko Tgfbr2iko aortas all displayed a similar but reduced level of Smad2 phosphorylation at various time points, indicating that loss of the canonical TGF-β signal is not the primary driver for the aortic phenotype of Alk5iko aortas. Meanwhile, the Alk5iko aortas produced 3-fold more pERK than Alk5f/f controls, and this elevation was completely abolished by the additional Tgfbr2 deletion. Pharmaceutical treatment of the Alk5iko mice with ERK inhibitor RDEA-119 significantly inhibited aortic dilation and prevented aortic wall from degeneration while those treated with vehicle control exhibited aortic dilation and intimal/medial tears. In conclusion, loss of Alk5 in SMCs triggers a non-Alk5 but Tgfbr2 dependent signal that promotes aortic aneurysm formation through exacerbating ERK activity.

Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome

VASA ◽  
2017 ◽  
Vol 46 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Alejandra María Zúñiga-Muñoz ◽  
Israel Pérez-Torres ◽  
Verónica Guarner-Lans ◽  
Elías Núñez-Garrido ◽  
Rodrigo Velázquez Espejel ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Aortic Aneurysms ◽  
Aortic Dilatation ◽  
Glutathione S Transferase ◽  
Reduced And Oxidized Glutathione ◽  
Total Antioxidant ◽  
Elevated Activity ◽  
Acute Dissection ◽  
Thoracic Aneurysms

Abstract. Background: Aortic dilatation in Marfan syndrome (MFS) is progressive. It is associated with oxidative stress and endothelial dysfunction that contribute to the early acute dissection of the vessel and can result in rupture of the aorta and sudden death. We evaluated the participation of the glutathione (GSH) system, which could be involved in the mechanisms that promote the formation and progression of the aortic aneurysms in MFS patients. Patients and methods: Aortic aneurysm tissue was obtained during chest surgery from eight control subjects and 14 MFS patients. Spectrophotometrical determination of activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO) index, carbonylation, total antioxidant capacity (TAC), and concentration of reduced and oxidized glutathione (GSH and GSSG respectively), was performed in the homogenate from aortic aneurysm tissue. Results: LPO index, carbonylation, TGF-β1, and GR activity were increased in MFS patients (p < 0.04), while TAC, GSH/GSSG ratio, GPx, and GST activity were significantly decreased (p < 0.04). Conclusions: The depletion of GSH, in spite of the elevated activity of GR, not only diminished the activity of GSH-depend GST and GPx, but increased LPO, carbonylation and decreased TAC. These changes could promote the structural and functional alterations in the thoracic aorta of MFS patients.

Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections

2015 ◽  
Vol 21 (28) ◽  
pp. 4061-4075 ◽  
Author(s):  
Julie Backer ◽  
Marjolijn Renard ◽  
Laurence Campens ◽  
Laura Mosquera ◽  
Anne Paepe ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms
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