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KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells (circRNA microarray)

ABSTRACT: Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216305 | GEO | 2022/12/14

REPOSITORIES: GEO

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KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells (mRNA microarray)

Project description:Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.

2022-12-14 | GSE216303 | GEO

KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells

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Endothelial inhibition of the glycolytic activator PFKFB3 induces tumor vessel normalization, impairs metastasis and improves chemotherapy

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Project description:To comprehensively understand the mechanism by which MYPT1 modulates the phenotypic switching of VSMCs after ischemic stroke, the proteins of cortical small vessel from MYPT1SMKO and WT mice subjected to MCAO or sham group were collected for proteomic screening.

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Project description:Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention.

2018-09-19 | GSE117963 | GEO

PFKFB3 drives renal fibrosis through promoting histone lactylation-mediated NF- B activation [RNA-seq]

Project description:Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease. However, the underlying mechanism remains largely unclear. Here, we observed that PFKFB3, a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells following ischemia-reperfusion injury in mice, as well as in multiple etiologies of chronic kidney disease patients. Proximal tubular epithelial-specific deletion of PFKFB3 significantly reduced renal lactate levels, mitigated inflammation and fibrosis, and preserved renal function in the IRI mouse model. To explore the mechanism of PFKFB3 in renal fibrosis, we performed RNA-sequencing (RNA-seq) on the kidney cortices from IRI mice. Of note, we found that PFKFB3-mediated kidney tubular glycolytic reprogramming markedly enhanced H4K12la lactylation. To further explore the potential functional significance of H4K12la in renal fibrosis, we performed genome-wide cleavage under targets and tagmentation (CUT&Tag) analysis to identify candidate genes regulated by H4K12la in sham and IRI kidney. Following CUT&Tag, H4K12la-associated DNAs were amplified using non-biased conditions, labeled, and sequenced with Illumina NovaSeq 6000.

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