Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55–65% V̇o2max) and tapering off at a higher intensity of exercise (85% V̇o2max). The mechanism underlying the reduced elastin fragmentation in Marfan mice involved reduction of the expression of matrix metalloproteinases 2 and 9 within the aortic wall. These findings present the first evidence of potential beneficial effects of mild exercise on the structural integrity of the aortic wall in Marfan syndrome associated aneurysm. Our finding that moderate, but not strenuous, exercise protects aortic structure and function in a mouse model of Marfan syndrome could have important implications for the medical care of young Marfan patients. NEW & NOTEWORTHY The present study provides conclusive scientific evidence that daily exercise can improve aortic health in a mouse model of Marfan syndrome associated aortic aneurysm, and it establishes the threshold for the exercise intensity beyond which exercise may not be as protective. These findings establish a platform for a new focus on promoting regular exercise in Marfan patients at an optimum intensity and create a paradigm shift in clinical care of Marfan patients suffering from aortic aneurysm complications.

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Anti-TGFβ (Transforming Growth Factor β) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316496 ◽

2021 ◽

Author(s):

Cristina Arce ◽

Isaac Rodríguez-Rovira ◽

Karo De Rycke ◽

Karina Durán ◽

Victoria Campuzano ◽

...

Keyword(s):

Growth Factor ◽

Aortic Aneurysm ◽

Mouse Model ◽

Marfan Syndrome ◽

Palliative Treatment ◽

Transforming Growth Factor ◽

Preventive Treatment ◽

Transforming Growth Factor Β ◽

Mrna Levels ◽

Tgfβ Signaling

Objective: We investigated the effect of a potent TGFβ (transforming growth factor β) inhibitor peptide (P144) from the betaglycan/TGFβ receptor III on aortic aneurysm development in a Marfan syndrome mouse model. Approach and Results: We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFβ signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfβ1 and Tgfβ2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFβ signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfβ1 and Tgfβ2 mRNA levels. Conclusions: P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFβ signaling during the early stages of aortic disease progression.

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The Effect of a Nonpeptide Angiotensin II Type 2 Receptor Agonist, Compound 21, on Aortic Aneurysm Growth in a Mouse Model of Marfan Syndrome

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000560 ◽

2018 ◽

Vol 71 (4) ◽

pp. 215-222 ◽

Cited By ~ 6

Author(s):

Peter Verbrugghe ◽

Jelle Verhoeven ◽

Marnick Clijsters ◽

Dominique Vervoort ◽

Jarne Schepens ◽

...

Keyword(s):

Angiotensin Ii ◽

Aortic Aneurysm ◽

Mouse Model ◽

Marfan Syndrome ◽

Receptor Agonist ◽

Aneurysm Growth ◽

Compound 21

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Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Circulation ◽

10.1161/circulationaha.120.051171 ◽

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.

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In vivo characterization of doxycycline-mediated protection of aortic function and structure in a mouse model of Marfan syndrome-associated aortic aneurysm

Scientific Reports ◽

10.1038/s41598-018-38235-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Jason Z. Cui ◽

Ling Lee ◽

Xiaoye Sheng ◽

Fanny Chu ◽

Christine P. Gibson ◽

...

Keyword(s):

Aortic Aneurysm ◽

Mouse Model ◽

Marfan Syndrome ◽

In Vivo Characterization

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Effects of Voluntary Exercise on Progression of Aortic Aneurysm in a Mouse Model of Marfan Syndrome

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.994.17 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Christine Gibson ◽

Ramona Alex ◽

Thomas Broderick ◽

Johana Vallejo ◽

Mitra Esfandiarei

Keyword(s):

Aortic Aneurysm ◽

Mouse Model ◽

Marfan Syndrome ◽

Voluntary Exercise

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Implications of Genetic Manipulation of Caveolin‐1 Protein Expression in a Mouse Model of Marfan Syndrome‐Associated Aortic Aneurysm

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.828.11 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Tala Curry ◽

Brikena Hoxha ◽

Nathan Johnson ◽

Tom L Broderick ◽

Johana Vallejo‐Elias ◽

...

Keyword(s):

Aortic Aneurysm ◽

Mouse Model ◽

Protein Expression ◽

Marfan Syndrome ◽

Genetic Manipulation ◽

Caveolin 1

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Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome

VASA ◽

10.1024/0301-1526/a000609 ◽

2017 ◽

Vol 46 (3) ◽

pp. 177-186 ◽

Cited By ~ 8

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.

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