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Latent TGF β binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation

ABSTRACT: Latent TGF β binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation

PROVIDER: PRJNA639152 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12005388_1.fastq.gz	Fastqsanger.gz
	SRR12005388_2.fastq.gz	Fastqsanger.gz
	SRR12005389_1.fastq.gz	Fastqsanger.gz
	SRR12005389_2.fastq.gz	Fastqsanger.gz
	SRR12005390_1.fastq.gz	Fastqsanger.gz

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Latent TGF β binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation

Project description:Aneurysm and dissection of the aortic root is a common cause of morbidity and mortality in Loeys-Dietz Syndrome (LDS) and Marfan Syndrome (MFS), where perturbations in TGF β signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling for mechanistic studies and pre-clinical drug discovery, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish larvae, homozygous for null mutations in latent TGF β binding proteins (ltbps) 1 and 3, develop rapid and severe aneurysmal dilatation of the aortic root equivalent, the outflow tract (OFT), after grossly unperturbed cardiac morphogenesis. The ventricle also becomes significantly dilated and upregulates stress-responsive genes, which likely reflects compensatory pathologic remodeling since ltbp1 and ltbp3 co-expression is restricted to the OFT. Similar to aneurysm tissue from LDS and MFS patients, the distended OFTs display evidence for hyperactivated TGF β signaling. Moreover, RNA-sequencing revealed significant overlap between the molecular signatures of diseased tissue from double knockout zebrafish and MFS mice. Lastly, chemical inhibition of the TGF β Type I receptor in wild-type embryos evoked similar OFT and ventricular dilation phenotypes, demonstrating that TGF β signaling is protective against these pathologies. The disease relevance of the mutant phenotype is further supported by recent family studies implicating genetic lesions in Ltbp3, and likely Ltbp1, as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that the unique advantages of zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small molecule suppressor screens.

2022-04-19 | GSE152389 | GEO

Latent TGFβ-binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation.

Project description:Aortic root aneurysm is a common cause of morbidity and mortality in Loeys-Dietz and Marfan syndromes, where perturbations in transforming growth factor beta (TGFβ) signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish devoid of the genes encoding latent-transforming growth factor beta-binding protein 1 and 3 (ltbp1 and ltbp3, respectively) develop rapid and severe aneurysm of the outflow tract (OFT), the aortic root equivalent. Similar to syndromic aneurysm tissue, the distended OFTs display evidence for paradoxical hyperactivated TGFβ signaling. RNA-sequencing revealed significant overlap between the molecular signatures of disease tissue from mutant zebrafish and a mouse model of Marfan syndrome. Moreover, chemical inhibition of TGFβ signaling in wild-type animals phenocopied mutants but chemical activation did not, demonstrating that TGFβ signaling is protective against aneurysm. Human relevance is supported by recent studies implicating genetic lesions in LTBP3 and, potentially, LTBP1 as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small-molecule suppressor screens. This article has an associated First Person interview with the first author of the paper.

| S-EPMC8990920 | biostudies-literature

Circulating microRNAs in patients with aneurysmal dilatation of coronary arteries

Project description:To understand the mechanism of coronary artery aneurysmal dilatation, we identified and compared the expression of circulating miRNAs in three groups of patients. Group 1 enrolled patients with aneurysmal dilatation of coronary arteries (n = 20), Group 2 included patients with angiographically confirmed coronary artery disease (CAD), whereas Group 3 included 20 patients with normal coronary arteries. The miRNAs were isolated from plasma and profiled using PCR arrays miRCURY LNA Serum/Plasma Focus PCR Panels. We demonstrated that the plasma miRNAs levels were significantly different in Group 1 in collation with Group 2 and Group 3 (fold change > 2 and p < 0.05). The comparison of Group 1 with Group 3 identified twenty-one significantly up-regulated and two down-regulated miRNAs in patients with aneurysmal coronary artery dilatation compared to the control groups. Moreover, we identified six up-regulated and two down-regulated miRNAs in patients with CAD compared to the controls. The third comparison revealed four up-regulated and three down-regulated miRNAs in Group 1, when compared to CAD patients. In conclusion, this study demonstrates the specific signature of plasma miRNA, namely up-regulated and down-regulated, in patients with abnormal dilatation of coronary arteries and the comparison between the groups consisting of atherosclerotic and control patients.

2022-03-18 | GSE198885 | GEO

Circulating microRNAs in patients with aneurysmal dilatation of coronary arteries

Project description:Circulating microRNAs in patients with aneurysmal dilatation of coronary arteries

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Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

Project description:Aortic aneurysms are dilations of the aorta that can rupture when left untreated. We used aneurysmal Fibulin-4R/R to further unravel the underlying mechanisms of aneurysm formation. RNA sequencing of 3-month-old Fibulin-4R/R aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of Fibulin-4R/R VSMCs by revealing increased SA-β-gal, p21 and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of Fibulin-4R/R|p21-Luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that Fibulin-4R/R aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK/STAT and TGF-β pathway inhibition as well as senolytic treatment on Fibulin-4R/R VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.

2024-04-30 | GSE265869 | GEO

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