PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing

Jia, Yiting; Mao, Chenfeng; Ma, Zihan; Huang, Jiaqi; Li, Wenqiang; Ma, Xiaolong; Zhang, Siting; Li, Meihong; Yu, Fang; Sun, Yingying; Chen, Jingzhou; Feng, Juan; Zhou, Yuan; Xu, Qingbo; Zhao, Ling; Fu, Yi; Kong, Wei

doi:10.1161/circresaha.122.321005

Cited by 30 publications

(18 citation statements)

References 72 publications

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“…Expanded Materials and Methods Tables S1-S4 Figures S1-S11 References 4,6,7,11,12,31,32,34,37,38,40,[55][56][57][58][59][60][61][62][63][64][65][66]…”

Section: Sources Of Fundingmentioning

confidence: 99%

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban

Ren,

Wei,

Liu

et al. 2024

Circulation Research

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BACKGROUND: Intracellular Ca 2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a) is responsible for the sequestration of cytosolic Ca 2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20 flox mice with Myh6 -Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca 2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 act as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

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“…Expanded Materials and Methods Tables S1-S4 Figures S1-S11 References 4,6,7,11,12,31,32,34,37,38,40,[55][56][57][58][59][60][61][62][63][64][65][66]…”

Section: Sources Of Fundingmentioning

confidence: 99%

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban

Ren,

Wei,

Liu

et al. 2024

Circulation Research

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“…Only hnRNPA1 and YBX1 interacted with circSMAD3 via RNA pull-down and RIP (Figure 5B-C). hnRNPA1, which is an RNA-binding protein, enhances arterial injury-induced neointima formation by modulating pre-RNA splicing 27 . Therefore, we considered hnRNPA1.…”

Section: Circsmad3 Interacts With Hnrnpa1 To Promote Its Degradation ...mentioning

confidence: 99%

CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation

Mei,

Zhou,

et al. 2023

Preprint

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AimsCircular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, making them attractive therapeutic agents for various vascular diseases. SMAD family is a downstream mediator of the canonical TGFβ signalling pathway and has been considered a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. Therefore, this study aimed to identify a functional circRNA derived from the SMAD family and elucidate its potential as an effective therapeutic agent for vascular proliferative diseases.Methods and ResultsWe initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed VSMC proliferation and phenotype switchingin vitroevidenced by morphological assays and ameliorated arterial injury-induced neointima formationin vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 (WDR76) to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated p53γ signalling pathway, and finally suppressed VSMC proliferation and phenotype switching.ConclusionOur study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.

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“…Recent studies suggest that metabolic adaption may be a key event for SMC phenotypic alteration. 11,12 Glucose metabolic reprogramming can promote the vascular SMC transit from contractile into synthetic phenotype. 11,12 Considering the functional importance of vascular SMC metabolic reprogramming and phenotypic alterations in facilitating injury-induced neointima formation, it is critical for us to uncover the intricate relationships between high blood pressure and vascular SMC metabolic reprogramming and phenotypic alterations in the context of the injury-induced neointimal formation.…”

mentioning

confidence: 99%

“…11,12 Glucose metabolic reprogramming can promote the vascular SMC transit from contractile into synthetic phenotype. 11,12 Considering the functional importance of vascular SMC metabolic reprogramming and phenotypic alterations in facilitating injury-induced neointima formation, it is critical for us to uncover the intricate relationships between high blood pressure and vascular SMC metabolic reprogramming and phenotypic alterations in the context of the injury-induced neointimal formation. In this study, droplets-based single-cell RNA-sequencing (scRNA-Seq) analysis 13 was applied to systematically profile the dynamic cellular states in the injured rat carotid arteries.…”

mentioning

confidence: 99%

Atlas of Cell Repertoire Within Neointimal Lesions Is Metabolically Altered in Hypertensive Rats

Sun,

Wu,

Zhang

et al. 2024

Hypertension

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BACKGROUND: High blood pressure has been suggested to accelerate vascular injury-induced neointimal formation and progression. However, little is known about the intricate relationships between vascular injury and hypertension in the context of arterial remodeling. METHODS: Single-cell RNA-sequencing analysis was used to depict the cell atlas of carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats with or without balloon injury. RESULTS: We found that hypertension significantly aggravated balloon injury-induced arterial stenosis. A total of 36 202 cells from carotid arteries with or without balloon injury were included in single-cell RNA-sequencing analysis. Cell composition analysis showed that vascular injury and hypertension independently induced distinct aortic cell phenotypic alterations including immune cells, endothelial cells (ECs), and smooth muscle cells. Specifically, our data showed that injury and hypertension-induced specific EC phenotypic alterations, and revealed a transition from functional ECs to hypermetabolic, and eventually dysfunctional ECs in hypertensive rats upon balloon injury. Importantly, our data also showed that vascular injury and hypertension-induced different smooth muscle cell phenotypic alterations, characterized by deferential expression of synthetic signatures. Interestingly, pathway analysis showed that dysregulated metabolic pathways were a common feature in monocytes/macrophages, ECs, and smooth muscle cells in response to injury and hypertension. Functionally, we demonstrate that inhibition of mitochondrial respiration significantly ameliorated injury-induced neointimal formation in spontaneously hypertensive rats. CONCLUSIONS: This study provides the cell landscape changes of the main aortic cell phenotypic alterations in response to injury and hypertension. Our findings suggest that targeting cellular mitochondrial respiration could be a novel therapeutic for patients with hypertension undergoing vascular angioplasty.

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PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing

Cited by 30 publications

References 72 publications

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban

CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation

Atlas of Cell Repertoire Within Neointimal Lesions Is Metabolically Altered in Hypertensive Rats

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