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Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells

ABSTRACT: Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells

PROVIDER: PRJNA1230731 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32547807_1.fastq.gz	Fastqsanger.gz
	SRR32547807_2.fastq.gz	Fastqsanger.gz
	SRR32547808_1.fastq.gz	Fastqsanger.gz
	SRR32547808_2.fastq.gz	Fastqsanger.gz
	SRR32547809_1.fastq.gz	Fastqsanger.gz

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Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells

Project description:Aortic aneurysm and dissection (AAD) is a life-threatening disease without effective pharmacological treatments. The progressive loss of vascular smooth muscle cells (VSMCs) is the fundamental pathophysiological basis for AAD, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and consequent prevention of vascular remodeling-related diseases. However, its role in AAD development requires further investigation. Here, we show that SIRT6 expression was significantly reduced in VSMCs of the thoracic aorta in AAD patients. Sirt6 deficiency in VSMCs dramatically accelerated angiotensin Ⅱ (Ang Ⅱ) infusion-induced AAD formation and rupture even without an Apoe-deficient background. In vitro studies demonstrated that Sirt6 deficiency led to mitochondrial dysfunction and accelerated VSMC senescence. Mechanistically, SIRT6 could bind and deacetylate NRF2, a key transcription factor for mitochondrial biogenesis, however, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang Ⅱ-induced mitochondrial dysfunctions in human aortic smooth muscle cells. More importantly, MDL-811 also mitigated AAD progression in mice. These findings suggest that SIRT6 plays a protective role in AAD development and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.

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

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

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Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm

Project description:Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.

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Gene expression changes in human thoracic and abdominal aortic aneurysm tissue

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High-throughput sequencing analysis of miRNAs expression profiles in the thoracic ascending aortic aneurysm (TAA) tissues and plasma samples.

Project description:In the present study, we evaluated miRNA expression profiles of 32 patient aortic aneurysm tissue and plasma samples using Illumina next-generation sequencing platform. A total of 20 miRNA were differentially expressed in tissues, 17 miRNAs - in plasma samples. Differentially expressed miRNAs determined in the present study could be applied for thoracic ascending aneurysm diagnosis.

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Vascular smooth muscle cell senescence instigates thoracic aortic aneurysm

Project description:Vascular smooth muscle cell senescence instigates thoracic aortic aneurysm

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PP2A attenuates thoracic aneurysm and dissection in mouse models of Marfan syndrome [RNA-seq]

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Project description:Aortic aneurysms is increasing as the human population ages. Pathological oxidative stress is implicated in development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line DAAO-TGTie2 that expresses yeast D-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TGTie2 mice, DAAO generates the reactive oxygen species hydrogen peroxide (H2O2) in endothelial cells only when provided with D-amino acids. When DAAO-TGTie2 mice are chronically fed D-alanine, the animals become hypertensive and develop abdominal but not thoracic aortic aneurysms. Generation of H2O2 in the endothelium leads to oxidative stress throughout the vascular wall. Proteomic analyses indicate that the oxidant-modulated protein kinase JNK1 is dephosphorylated by the phophoprotein phosphatase DUSP3 in abdominal but not thoracic aorta, causing activation of KLF4-dependent transcriptional pathways that trigger phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocks aneurysm formation caused by chemogenetic oxidative stress. These studies establish that regional differences in oxidant-modulated signaling pathways lead to differential disease progression in discrete vascular beds, and identify DUSP3 as a potential pharmacological target for the treatment of aortic aneurysms.

2025-02-18 | PXD060700 | Pride

Gene expression changes in human thoracic and abdominal aortic aneurysm tissue

Project description:Gene expression changes in human thoracic and abdominal aortic aneurysm tissue

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