Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

The role of Ninjurin-1 deficiency in Jak2V617F clonal hematopoiesis mediated atherosclerosis plaque progression

ABSTRACT: Clonal haematopoiesis of indeterminate potential (CHIP) involves age-related acquisition and expansion of genes frequently mutated in haematologic malignancies (e.g. DNMT3A, TET2, or JAK2). JAK2 heightens cardiovascular disease (CVD) risk. The mechanism, although incompletely understood, involves pyroptosis and plasma membrane rupture, mediated by Ninjurin-1 (NINJ1), followed by release of damage-associated molecular patterns and cytokines. Moreover, individuals with JAK2-CHIP have elevated levels of circulating interleukin-17 receptor-A (IL-17RA). IL-17RA signalling, implicated in autoimmunity, paradoxically may have a protective role in atherogenesis. IL-17A produced by T helper 17 (Th17) cells binding to IL-17RA in myeloid cells may induce a TREM2 macrophage response to create a feedback loop and dampen further inflammation. The proteomic association between JAK2-CHIP and IL-17RA, along with the potential role of IL-17RA signalling in atherosclerosis, led us to hypothesize that IL-17RA signalling modifies CVD risk among individuals with JAK2-CHIP.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Cheng-Chieh Hsu

PROVIDER: E-MTAB-16375 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Interleukin-17 receptor-A signalling: atheroprotective role in JAK2 clonal haematopoiesis.

Zhao Kun K Hsu Cheng-Chieh CC Pershad Yash Y Vlasschaert Caitlyn C Corty Robert W RW Wang Nan N Heimlich Jonathan Brett JB Tall Alan R AR Bick Alexander G AG

European heart journal 20251201 48

PMID: 40986427

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Project description:The nitric oxide synthase (NOS) co-factor, tetrahydrobiopterin (BH4), is a redox-active molecule that regulates nitric oxide (NO) and reactive oxygen species (ROS) production by NOS, and is an example of redox-dependent signalling in the endothelium that underlies both the maintenance of vascular homeostasis and the development of cardiovascular disease (CVD). Loss of endothelial BH4 is observed in CVD states and results in decreased NO production and increased ROS generation by endothelial NO synthase (uncoupling). Genetic mouse models of augmented endothelial BH4 synthesis have shown proof of concept that endothelial BH4 can alter CVD pathogenesis. However, clinical trials of BH4 therapy in vascular disease have been limited by systemic oxidation and limited endothelial uptake of BH4, highlighting the need to explore the wider roles of BH4 in order to find novel therapeutic targets. In this study we aim to elucidate the effects of BH4 depletion on mitochondrial function and bioenergetics using targeted knockdown of the BH4 synthetic enzyme GTPCH in vitro. Knockdown of GTPCH (and, therefore, intracellular BH4 levels) by >90% lead to a striking induction of ROS generation in the mitochondria of murine endothelial cells. This effect was likewise observed in BH4 depleted GCH fibroblasts devoid of NOS, indicating a novel NOS-independent role for BH4 in mitochondrial redox signalling. Furthermore, this BH4-dependent, mitochondrial-derived ROS oxidized mitochondrial BH4 and is seen alongside distinct changes in the thioredoxin and glutathione antioxidant pathways, revealed by mass spectrometry using an unbiased proteomic approach. These changes are accompanied by a modest increase in mitochondrial size, attenuated respiratory function, and marked changes in the cellular metabolic profile; including succinate accumulation. Taken together, these data reveal a novel NOS-independent role for BH4 in the regulation of mitochondrial redox signalling and metabolism.

Dataset Information

The role of Ninjurin-1 deficiency in Jak2V617F clonal hematopoiesis mediated atherosclerosis plaque progression

Publications

Interleukin-17 receptor-A signalling: atheroprotective role in JAK2 clonal haematopoiesis.

Similar Datasets

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