Dataset Information

Early IKKb-dependent anabolic and fibrotic signatures govern vascular smooth muscle cells fate and abdominal aortic aneurysm development

ABSTRACT: Aims Abdominal aortic aneurysm (AAA) is a complex aortic disease define by a dilatation of the infrarenal aorta and the most common form of aneurysm in humans. Whereas inflammation contribute to AAA development, quenching vascular inflammation using classical pharmacological approaches or inhibiting the immune system does not influence the progression of AAA in humans indicating the lack of a complete picture on the molecular events that drive this aortopathy. This study was designed to comprehend the earliest molecular indicators, aiming to pinpoint a biological target associated with the latter. Methods and results Using ApoE-deficient mice fed with a standard diet and infused with Angiotensin II (Ang II), we conducted bulk RNA-sequencing analysis on suprarenal (SRA) regions obtained from both unchallenged and challenged WT mice, specifically examining responses 24 hours after Ang II infusion to capture the initial phases of aortic stress response. We further created a unique model of hyperlipidemic mice in which the expression of IKK can be conditionally (via tamoxifen injection) suppressed in vascular SMCs (CreERT2 under the control of the Acta2 promoter). The development of AAA was evaluated using in situ examination and quantified using RT-qPCR, immunohistochemistry and fluorescence microscopy. Cultured vascular SMC were exposed to the selective IKK inhibitor MLN120b and the expression levels of phenotypic markers KLF4, -Catenin and CTGF were addressed using cellular extracts and immunoblot analysis. Results RNASeq data support the presence of early anabolic events in SRA regions detailing activation of the mTORC1 pathway, which paralleled cellular processes including mitochondria, ribosome and sterol biosynthesis and the Unfolded Protein Response (UPR). Conditional deletion of the Ikbkb gene in vascular SMCs significantly reduces the incidence of SRA lesions as well as the rate of aneurysm ruptures in animals exposed to Ang II. In situ analysis further demonstrated that the protection conferred by the lack of IKK expression in vascular SMC is associated with reduced inflammatory response, the preservation of the contractile over the degradative vascular SMC phenotypes and the absence of anabolic and fibrotic signatures. Conclusion Our data not only reinforce the major roles play by vascular SMC in the rapid adaptation leading to the deleterious remodeling of the vascular wall and aortic lesions but also support a paradigm aiming at repositioning the efforts focusing on anabolic rather than inflammatory events.

ORGANISM(S): Mus musculus

PROVIDER: GSE265897 | GEO | 2025/05/28

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Objective: Angiotensin-II (Ang-II) drives pathological vascular wall remodeling in hypertension and abdominal aortic aneurysm (AAA). Previous studies showed that the phosphatase activity of calcineurin (Cn) mediates Ang-II-induced AAA, but the cell type involved in the action of Cn in AAA formation remained unknown. Methods: Smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/- mice, respectively) were created and assessed for Ang-II-induced AAA formation and hypertension vs controls. Osmotic minipumps were used to administer Ang-II and cyclosporine A (CsA), a pharmaceutical Cn inhibitor. AAA formation and hypertension were monitored by ultrasonography, arterial blood pressure monitoring, and histological analysis. Deep RNA sequencing was used to identify the Ang-II-regulated transcriptome sensitive to Cn deletion or pharmacological inhibition. Arterial and SMC contractility were also assessed. Results: Cn expressed in SMCs, but not ECs, was required for Ang-II-induced AAA. SMC Cn also played an unexpected structural role in the early onset and maintenance of Ang-II-induced hypertension independently of Cn phosphatase activity. Nearly 90% of the genes regulated by Ang-II in the aorta required Cn expression in SMCs. Cn orchestrated, independently of its enzymatic activity, the induction by Ang-II of a gene expression program closely related to SMC contractility and hypertension. Cn deletion in SMCs, but not its pharmacological inhibition, impaired the regulation of arterial contractility. Among the genes whose regulation by Ang-II required Cn expression but not its phosphatase activity, Serpine1 was critical for Ang-II-induced hypertension. Indeed, pharmacological inhibition of PAI-1, the protein encoded by Serpine1, impaired SMCs contractility and regressed hypertension. Conclusions: Whereas the phosphatase activity of Cn mediates Ang-II-induced AAA, a phosphatase-independent action of SMC Cn underlies blood pressure regulation by orchestrating a gene expression program closely related to contractility regulation and hypertension.

Project description:Background: Abdominal Aortic Aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. Activating transcription factor (ATF) 3 has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 in AAA development and progression remains elusive. Methods: Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II-induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell (VSMC)-specific ATF3 knockdown or overexpressed mice by recombinant adeno-associated virus serotype 9 (rAAV9) vectors carrying ATF3, or shRNA-ATF3 with SM22α promoter were used in AngII (angiotensin II) induced AAA mice. In human and murine VSMCs, gain or loss of function experiments were performed to investigate the role of ATF3 in VSMC proliferation and apoptosis. Results: In both AngII-induced AAA mice and AAA patients, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in VSMC promoted AAA formation in AngII-induced AAA mice. PDGFRB was identified as the target of ATF3, which mediated VSMC proliferation in response to TNF-alpha at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our ChIP results also demonstrated that the recruitment of NFκB1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (Andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development. Conclusions: Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.

Dataset Information

Early IKKb-dependent anabolic and fibrotic signatures govern vascular smooth muscle cells fate and abdominal aortic aneurysm development

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets