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Inhibition of Intimal CX3CR1+ Macrophages Mitigates Thoracic Aortic Aneurysm Progression in Marfan Syndrome

ABSTRACT: Inhibition of Intimal CX3CR1+ Macrophages Mitigates Thoracic Aortic Aneurysm Progression in Marfan Syndrome

PROVIDER: PRJNA1048842 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27078943_1.fastq.gz	Fastqsanger.gz
	SRR27078943_2.fastq.gz	Fastqsanger.gz
	SRR27078944_1.fastq.gz	Fastqsanger.gz
	SRR27078944_2.fastq.gz	Fastqsanger.gz

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Inhibition of Intimal CX3CR1+ Macrophages Mitigates Thoracic Aortic Aneurysm Progression in Marfan Syndrome

Project description:Current understanding on the pathogenesis of thoracic aortic aneurysms (TAAs) in Marfan Syndrome (MFS) mainly focuses on vascular smooth muscle cell (VSMC) pathologies. Whether immune cell-mediated inflammation drives the progression of TAAs is still elusive. Using single-cell RNA sequencing, a subset of macrophages highly expressing CX3CR1 and mainly locating in the aortic intima was identified in aortic root and ascending aortas from Fbn1C1041G/+ mice, and further validated in MFS patients. Specific elimination of CX3CR1+ macrophages by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression, suggesting their pathogenic action. Using monoclonal antibodies Adalimumab and Teprotumumab to respectively neutralize the proinflammatory cytokines TNFalpha and IGF1 produced by CX3CR1+ macrophages from MFS patients substantially suppressed CX3CR1+ macrophage-mediated inflammation in MFS patient-specific induced pluripotent stem cell (iPSC)-derived VSMCs. Furthermore, bone marrow transplantation and parabiosis using Cx3cr1GFP/+ mice revealed the intimal CX3CR1+ macrophages derived from circulating monocytes. Administration of CCR2 antagonist RS504393 to inhibit monocyte infiltration significantly reduced intimal CX3CR1+ macrophages and subsequently alleviated TAA development in Fbn1C1041G/+ mice. In conclusion, intimal CX3CR1+ macrophages mediated TAA formation through paracrinally causing VSMC inflammation. Targeting intimal CX3CR1+ macrophages would be a promising anti-inflammatory strategy in TAA therapy for MFS.

2024-12-10 | GSE249352 | GEO

Aortic smooth muscle cell phenotype modulation during Marfan syndrome aneurysm formation

Project description:We report dynamic temporal and spatial smooth muscle cell phenotype modulation using aortic single cell RNA sequencing in a murine model of Marfan syndrome (Fbn1C1041G/+) and littermate controls. Aortic root/ascending aortic tissue samples from both genotypes were studied at 4 and 24 weeks of age. The non-aneurysmal descending thoracic aorta was also studied at 24 weeks. Finally human aortic tissue from a Marfan syndrome patient undergoing aneurysm repair surgery was studied.

2020-06-30 | GSE153534 | GEO

Subcellular pathways shared by afflicted patients and mutant mice identify a new drug treatment for aortic aneurysm in Marfan syndrome

Project description:We analyzed differentially expressed genes in smooth muscle cells derived from the thoracic aorta of Marfan Syndrome (MFS) patients and control subjects to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify a potential drug treatment to mitigate TAA progression. We analyzed differentially expressed genes in whole aorta of P16 MFS mice vs WT mice to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify baclofen as a potential drug treatment to mitigate TAA progression. The effect of baclofen on gene expression in WT and MFS was documented in P60 mice that received treatment since P16.

2019-11-18 | GSE128101 | GEO

17 -estradiol impedes aortic root dilation and rupture in male Marfan mice

Project description:Thoracic aortic aneurysms have a higher prevalence in male patients compared to female patients. Marfan syndrome causes a hereditary form of TAA with dilation of the aortic root. Male patients with Marfan syndrome are more likely than women to have aortic dilation and dissection and mouse models of Marfan syndrome demonstrate larger aortic roots in males compared to females even after adjustment for body size. Similar sex disparities are present in patients and models of abdominal aortic aneurysms where estrogen has been demonstrated to attenuate aneurysm formation perhaps through anti-inflammatory mechanisms. In this study we demonstrate the effects of estrogen on aortic dilation and rupture in a Marfan mouse model and we investigate if these effects operate through suppression of complement components of the immune system.

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Inhibition of the multifunctional homeodomain-interacting protein kinase 2 (HIPK2) alleviates thoracic aortic disease in mice with progressively severe Marfan syndrome

Project description:Thoracic aortic aneurysm (TAAs) are a severe complication in Marfan Symdrome (MFS), often leading to dissection and premature death. To identify potential drug targets for the treatment for TAAs we used gene expression profiles from MFS mice and patients to predict kinases that regulate gene expression. Among the top predictions was the kinase HIPK2. Ubiquitous post-natal inactivation of the HIPK2 gene, as well as chronic administration of an allosteric inhibitor of HIPK2/Smad3 interaction, increased the survival of MFS mice and improved multiple surrogate parameters.

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Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).

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Project description:Although abnormal TGFbeta signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, the precise role of TGFbeta signaling in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to investigate the role of TGFbeta signaling in molecular pathways of pathogenesis associated with development of aortic aneurysm and aortic rupture. This study reports an isoform-specific effect of TGFbeta in MFS aortic disease and the effects of deleting the first hybrid domain of fibrillin-1 on TGFbeta signaling. Distinct molecular differences in mouse models of aneurysm (Fbn_GT-8_plus), of aneurysm and rupture (Fbn1_GT-8_H1delta), and of microdissection (Fbn1_H1delta_plus) were identified, which associated with TGFbeta signaling and extracellular matrix composition, possibly contributing to the development of dissection and rupture. These findings offer new insights into the pathophysiological mechanisms that potentially drive initiation of aortic dissection and could pave the way for development of new treatment targets of aortic disease.

2023-10-09 | PXD036222 | Pride

Dissecting aortic aneurysm in Marfan syndrome is associated with losartan-sensitive transcriptomic modulation of aortic cells

Project description:To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) leading to acute aortic dissection, we used single-cell RNA sequencing to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result,MFSmod were identified only in the aorta of Fbn1mgR/mgR mice. In situ hybridizations of diagnostic transcripts located MFSmod cells to the intima of Fbn1mgR/mgR aortas. Consistent with angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients.

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Smooth muscle cell-specific Klf4 deletion in Marfan syndrome aortic root aneurysm

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2022-08-23 | GSE206227 | GEO

Gene expression changes in human thoracic and abdominal aortic aneurysm tissue

Project description:To determine how gene expression is altered in aorta tissue in response to aortic aneurysm disease. Thoracic or abdominal aorta tissue was isolated from patients requiring surgery due to aortic aneurysm or other (control) reason.

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