MIAT-DHX9 spatiotemporal expression drives venous neointimal hyperplasia through nucleolar homeostasis and mitotic progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus Norvegicus
SUBMITTER: 
Yingxin Qi
PROVIDER: PXD068863 | iProX | Fri Sep 26 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Venous neointimal hyperplasia, characterized by the abnormal proliferation of smooth muscle cells (SMCs), represents a critical contributor to vascular stenosis and therapeutic failure in vascular interventions. Here, we identified a novel role of spatiotemporal nucleolar expression of DExH-box helicase 9 (DHX9) and its binding partner, the long non-coding RNA (lncRNA) MIAT in venous neointimal pathogenesis. In normal SMCs, DHX9 transiently localized to nucleoli during the early S phase. Pathologically, endogenous-activated MIAT facilitated nucleolar DHX9 location and its interaction with PARP1. Activated-MIAT induced mitotic spindle pole location of DHX9 which was destroyed by PARP inhibitor. MIAT also drove SMCs proliferation by accelerating cell cycle progression. While depleting MIAT or DHX9 led to remarkable nucleolar subphase disruption, mitotic breakage-fusion-bridge, and DNA damage. Of note, nucleolar-associated morphology phenotypes analyzed with deep learning are determined to be valuable biomarkers for assessing cellular status and disease progress. MIAT was repressed in cultured human veins, reducing SMCs proliferation and vascular intimal hyperplasia. These results establish the MIAT-DHX9 axis as the central regulator of venous SMCs in arteriovenous fistula and venous graft models. Our study may provide a new avenue to destroy the pathologic spatiotemporal function of DHX9 by targeting MIAT in intimal hyperplasia.
2025-09-25 | GSE308756 | GEO
Project description:Venous neointimal hyperplasia, characterized by the abnormal proliferation of smooth muscle cells (SMCs), represents a critical contributor to vascular stenosis and therapeutic failure in vascular interventions. Here, we identified a novel role of spatiotemporal nucleolar expression of DExH-box helicase 9 (DHX9) and its binding partner, the long non-coding RNA (lncRNA) MIAT in venous neointimal pathogenesis. In normal SMCs, DHX9 transiently localized to nucleoli during the early S phase. Pathologically, endogenous-activated MIAT facilitated nucleolar DHX9 location and its interaction with PARP1. Activated-MIAT induced mitotic spindle pole location of DHX9 which was destroyed by PARP inhibitor. MIAT also drove SMCs proliferation by accelerating cell cycle progression. While depleting MIAT or DHX9 led to remarkable nucleolar subphase disruption, mitotic breakage-fusion-bridge, and DNA damage. Of note, nucleolar-associated morphology phenotypes analyzed with deep learning are determined to be valuable biomarkers for assessing cellular status and disease progress. MIAT was repressed in cultured human veins, reducing SMCs proliferation and vascular intimal hyperplasia. These results establish the MIAT-DHX9 axis as the central regulator of venous SMCs in arteriovenous fistula and venous graft models. Our study may provide a new avenue to destroy the pathologic spatiotemporal function of DHX9 by targeting MIAT in intimal hyperplasia.
2025-09-25 | GSE308700 | GEO
Project description:MIAT-DHX9 spatiotemporal expression drives venous neointimal hyperplasia through nucleolar homeostasis and mitotic progression
| PRJNA1332560 | ENA
Project description:MIAT-DHX9 spatiotemporal expression drives venous neointimal hyperplasia through nucleolar homeostasis and mitotic progression.
| PRJNA1332655 | ENA
Project description:Ischemic/hypoxic injury significantly damages vascular function, detrimentally im-pact-ing patient outcomes. Changes in mitochondrial structure and function are closely associated with ischemia/hypoxia-induced vascular dysfunction. The mecha-nism of this process remains elusive. Using rat models of ischemia and hypoxic vas-cular smooth muscle cells (VSMCs), we combined transmission electron microscopy, super-resolution microscopy, and metabolic analysis to analyze the structure and function change of mitochondrial cristae. Multi-omics approaches revealed arginase 1 (Arg1) upregulation in ischemic VSMCs, confirmed by in vivo and in vitro knock-out models showing Arg1's protective effects on mitochondrial cristae, mitochondrial and vascular function, and limited the release of mtDNA. Mechanistically, Arg1 in-teracting with Mic10 led to mitochondrial cristae remodeling, together with hypox-ia-induced VDAC1 lactylation resulting in the opening of MPTP and release of mtDNA of VSMCs. The released mtDNA led to PANoptosis of VSMCs via activation of the cGAS-STING pathway. ChIP-qPCR results demonstrated that lactate-mediated Arg1 up-regulation was due to H3K18la upregulation. VSMCs targeted nano-material PLGA-PEI-siRNA@PM-α-SMA (NP-siArg1) significantly improved vascular dysfunction. This study uncovers a new mechanism of vascular dysfunction following ischemic/hypoxic injury: a damaging positive feedback loop mediated by lactate-regulated Arg1 expression between the nucleus and mitochondria, leading to mitochondria cristae disorder and mtDNA release, culminating in VSMCs PANopto-sis. Targeting VSMCs Arg1 inhibition offers a potential therapeutic strategy to alle-viate ischemia/hypoxia-induced vascular impairments
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Project description:Background: Despite transcriptional control mechanisms of VSMC osteogenic transition having been extensively studied, posttranscriptional regulation is still awaiting elucidation. In the present study, we explore the mechanism of THOC5-dependent VSMCs osteochondrogenic switching. Methods: Von Kossa staining and immunohistochemistry staining were used to detect calcification and expression of THOC5 respectively. Thoc5 shRNA and Thoc5 overexpression lentivirus were used to modulate the expression of Thoc5. RNA-Seq combined with RIP-Seq was used to explore the target mRNAs that directly bind to THOC5, and FISH was used to confirm its subcellular localization. Results: Immunohistochemical staining showed significantly increased THOC5 expression in the calcified artery of CKD patients. Besides, calcification-induced increase of THOC5 expression was found in both in vivo and in vitro calcification models. The overexpression of Thoc5 relieves the calcification and osteogenic differentiation of VSMCs significantly in vitro, which is mainly manifested by the reduction of calcium ion deposition and the decreased expression of osteogenic markers. Furthermore, RNA-Seq revealed that THOC5 overexpression in osteogenic-induced VSMCs closely resembled the gene expression changes induced on TGF-β treatments in cultured VSMCs. In addition, overexpression of THOC5 alleviates the exacerbation of calcification in vivo. Our previous studies found that THOC5 displayed limited binding to VSMCs genomic DNA, so RIP-Seq was selected to detect target genes of THOC5. It was found that THOC5 directly interacts with Guanylate exchange factors (GEFs) mRNAs, and is required for their export. Thereby THOC5 maintaining RhoA GTPase activation contributes to increasing the expression of VSMCs contraction marker, which maintains the contraction phenotype of VSMCs. ROCK (Rho-kinase) inhibitor Y-27632 reversed the protective role of THOC5 on osteoblastic transdifferentiation and calcification, as well as the maintenance of the spindle morphology of VSMCs. Conclusions: Our data introduce the binding of THOC5 to GEFs as a novel mechanism contributing to maintaining VSMCs homeostasis and imply THOC5 as a potential intervention node for vascular calcification diseases.
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