Gene‐dosage effect of <i>Pfkfb3</i> on monocyte/macrophage biology in atherosclerosis

Guo, Shuai; Li, Anqi; Fu, Xiaodong; Zou, Li; Cao, Kaixiang; Song, Mingchuan; Huang, Shuqi; Li, Ziling; Yan, Jingwei; Wang, Litao; Dai, Xiaoyan; Feng, Du; Wang, Yong; He, Jun; Huo, Yuqing; Xu, Yiming

doi:10.1111/bph.15926

Cited by 15 publications

(13 citation statements)

References 39 publications

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“…70 Yet, another study indicated that PFBFK3 loss impaired macrophage efferocytosis and exacerbated atherosclerosis. 71 Even more results showed that partial myeloid knockdown of PFKFB3 did not affect atherosclerosis. 72 Nonetheless, the critical significance of PFKFB3 in human atherosclerosis and cerebrovascular events is evident and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events

Tan,

Liang,

Yang

et al. 2023

ATVB

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BACKGROUND: Carotid atherosclerosis is a chronic inflammatory disorder and is responsible for the vast majority of ischemic strokes. Inappropriate innate and adaptive immune responses synergize with malfunctional vascular wall cells to cause atherosclerotic lesions. Yet, functional characteristics of specific immune and endothelial cell subsets associated with atherosclerosis and cerebrovascular events are poorly understood. METHODS: Here, using single-cell RNA sequencing, the unprecedentedly largest data set from 20 patients’ carotid artery plaques and paired peripheral blood mononuclear cells was generated, with which an ultra-high-precision cellular landscape of the atherosclerotic microenvironment involving 372 070 cells was depicted. RESULTS: Compared with peripheral blood mononuclear cells, 3 plaque-specific T-cell subsets exhibiting proatherogenic features of both activation and exhaustion were identified. Strikingly, usually antiatherogenic, CD4 + FOXP3 + regulatory T cells from plaques of patients with symptomatic disease acquired proinflammatory properties by probably converting to T helper 17 and T helper 9 cells, while CD4 + NR4A1 + /C0 and CD8 + SLC4A10 + T cells related to cerebrovascular events possessed atherogenic attributes including proinflammation, polarization, and exhaustion. In addition, monocyte-macrophage dynamics dominated innate immune response. Two plaque-specific monocyte subsets performed diametrically opposed functions, EREG + monocytes promoted cerebrovascular events while C3 + monocytes are anti-inflammatory. Similarly, IGF1 + and HS3ST2 + macrophages with classical proinflammatory M1 macrophage features were annotated and contributed to cerebrovascular events. Moreover, SULF1 + (sulfatase-1) endothelial cells were also found to participate in cerebrovascular events through affecting plaque vulnerability. CONCLUSIONS: This compendium of single-cell transcriptome data provides valuable insights into the cellular heterogeneity of the atherosclerotic microenvironment and the development of more precise cardiovascular immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events

Tan,

Liang,

Yang

et al. 2023

ATVB

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“…Inhibiting macrophage proliferation using antibodies against MCSF and c-fms also hinders renal injury and kidney fibrosis ( 58 – 62 ). PFKFB3 is predominantly expressed in Ly-6C hi myeloid cells and provides energy for cell motility ( 38 ). Loss of Pfkfb3 impaired myeloid cell infiltration into the vessel wall and lung ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…F-2,6-P2 serves as a potent allosteric activator of 6-phosphofructo-1-kinase (PFK-1), one of key rate-limiting enzymes in glycolysis ( 34 ). Previous studies utilizing mice deficient in myeloid Pfkfb3 have demonstrated its role in suppressing ocular angiogenesis ( 35 , 36 ), pulmonary hypertension ( 37 ), and atherosclerosis ( 38 ). Metabolic shifting to glycolysis has been noted in renal repair and fibrosis development with renal acidosis developed after the accumulation of lactate ( 39 , 40 ).…”

Section: Introductionmentioning

confidence: 99%

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis

Yang,

Huo,

Cai

et al. 2023

Front. Immunol.

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Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby’s group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3ΔMϕ) and their wild type littermates (Pfkfb3WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3ΔMϕ mice compared to Pfkfb3WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.

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“…19 PFKFB3-mediated glycolysis in vascular cells has a critical role in the pathogenesis of cardiovascular disease. Recent studies have demonstrated that inhibition of PFKFB3mediated glycolysis reduces pathological angiogenesis, 20,21 hampers the progression of atherosclerosis, 22,23 and attenuates the development of pulmonary hypertension. 24,25 However, whether PFKFB3-mediated glycolysis regulates vascular calcification is unclear.…”

Section: Introductionmentioning

confidence: 99%

PFKFB3‐driven vascular smooth muscle cell glycolysis promotes vascular calcification via the altered FoxO3 and lactate production

Chen,

Yu,

Tan

et al. 2023

The FASEB Journal

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A link between increased glycolysis and vascular calcification has recently been reported, but it remains unclear how increased glycolysis contributes to vascular calcification. We therefore investigated the role of PFKFB3, a critical enzyme of glycolysis, in vascular calcification. We found that PFKFB3 expression was upregulated in calcified mouse VSMCs and arteries. We showed that expression of miR‐26a‐5p and miR‐26b‐5p in calcified mouse arteries was significantly decreased, and a negative correlation between Pfkfb3 mRNA expression and miR‐26a‐5p or miR‐26b‐5p was seen in these samples. Overexpression of miR‐26a/b‐5p significantly inhibited PFKFB3 expression in VSMCs. Intriguingly, pharmacological inhibition of PFKFB3 using PFK15 or knockdown of PFKFB3 ameliorated vascular calcification in vD3‐overloaded mice in vivo or attenuated high phosphate (Pi)‐induced VSMC calcification in vitro. Consistently, knockdown of PFKFB3 significantly reduced glycolysis and osteogenic transdifferentiation of VSMCs, whereas overexpression of PFKFB3 in VSMCs induced the opposite effects. RNA‐seq analysis and subsequent experiments revealed that silencing of PFKFB3 inhibited FoxO3 expression in VSMCs. Silencing of FoxO3 phenocopied the effects of PFKFB3 depletion on Ocn and Opg expression but not Alpl in VSMCs. Pyruvate or lactate supplementation, the product of glycolysis, reversed the PFKFB3 depletion‐mediated effects on ALP activity and OPG protein expression in VSMCs. Our results reveal that blockade of PFKFB3‐mediated glycolysis inhibits vascular calcification in vitro and in vivo. Mechanistically, we show that FoxO3 and lactate production are involved in PFKFB3‐driven osteogenic transdifferentiation of VSMCs. PFKFB3 may be a promising therapeutic target for the treatment of vascular calcification.

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Gene‐dosage effect of Pfkfb3 on monocyte/macrophage biology in atherosclerosis

Cited by 15 publications

References 39 publications

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events

Single-Cell Transcriptomics Reveals Crucial Cell Subsets and Functional Heterogeneity Associated With Carotid Atherosclerosis and Cerebrovascular Events

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis

PFKFB3‐driven vascular smooth muscle cell glycolysis promotes vascular calcification via the altered FoxO3 and lactate production

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