Platelet-Derived TGF (Transforming Growth Factor)-β1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation

Zhu, Ying; Shu, Dan; Gong, Xue; Li, Meng; Qian, Feng; Zeng, Xiangbin; Zhang, Han; Gao, Jiahui; Guo, Yawei; Liu, Luman; Ma, Rong; Zhu, Liping; Hu, Qinghua; Ming, Zhang-Yin

doi:10.1161/hypertensionaha.121.18684

Cited by 21 publications

(13 citation statements)

References 47 publications

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“…Platelets can release multiple cytokines to mediate the functions of immune cells 56 . Platelet-derived TGF-β contributes to the pathogenesis of pulmonary arterial hypertension 57 , and TGF-β contributes to the malignant transformation of the tumor microenvironment 58 . Furthermore, TGF-β is beneficial for establishing an immunosuppressive microenvironment 59 , which promotes macrophage polarization to the M2 phenotype 60 and accelerates tumor development.…”

Section: Discussionmentioning

confidence: 99%

Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages

Chen¹,

Gong²,

Zhao³

et al. 2023

Theranostics

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Rationale: Platelets can influence the progression and prognosis of colorectal cancer (CRC) through multiple mechanisms, including crosstalk with tumor-associated macrophages (TAMs). However, the mechanisms underlying the crosstalk between platelets and TAMs remain unclear. The present study aimed to investigate the role of intratumoral platelets in regulating the function of TAMs and to identify the underlying mechanisms. Methods: The interaction of platelets with macrophages was assessed in the presence or absence of the indicated compounds in vivo . An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC mouse model was used to investigate the role of platelets in controlling CRC development. Multiplexed immunofluorescence staining, fluorescence-activated cell sorting (FACS), and RNA sequence analysis were used to examine the changes in TAMs. TAMs and bone marrow-derived macrophages (BMDMs) were treated with the indicated compounds or siRNA against specific targets, and the expression levels of signal transducer and activator of transcription 1 (STAT1), c-Jun N-terminal kinase (JNK), and P-selectin glycoprotein ligand-1 (PSGL-1) were measured by Western blotting. The mRNA expression levels of complement 5 ( C5 ), complement 5a receptor 1 ( C5ar1 ), Arginase 1 ( Arg1 ) and Il10 were measured by real-time RT-PCR, and the complement 5a (C5a) concentration was measured by ELISA. The dual-luciferase reporter assay and ChIP assay were performed to examine the potential regulatory mechanisms of platelet induction of C5 transcription in TAMs. Results: In our study, we found that an increase in platelets exacerbated CRC development, while inhibiting platelet adhesion attenuated tumor growth. Platelets signal TAMs through P-selectin (CD62P) binding to PSGL-1 expressed on TAMs and activating the JNK/STAT1 pathway to induce the transcription of C5 and the release of C5a, shifting TAMs toward a protumor phenotype. Inhibiting the C5a/C5aR1 axis or PSGL-1 significantly reduced CRC growth. Conclusions: An increase in intratumoral platelets promoted CRC growth and metastasis by CD62P binding to PSGL-1 expressed on TAMs, leading to JNK/STAT1 signaling activation, which promoted C5 transcription and activated the C5a/C5aR1 axis in TAMs. Our study examined the mechanism of the crosstalk between platelets and TAMs to exacerbate CRC development and proposed a potential therapeutic strategy for CRC patients.

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Section: Discussionmentioning

confidence: 99%

Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages

Chen¹,

Gong²,

Zhao³

et al. 2023

Theranostics

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“…39 Heightened PKM2 expression and glycolytic activity are also observed in TGF-β-stimulated PASMCs isolated from rodent PAH models, via activation of the mTOR (mammalian target of rapamycin)/c-Myc (cellular myelocytomatosis oncogene)/PTBP1-hnRNPA1 (heterogenous nuclear ribonucleoprotein A1) pathway; however, its relationship to miR-124 expression and warrants confirmation. 40 The phenotypic plasticity of vascular smooth muscle cells (VSMCs) is widely recognized, and their "phenotypic switching" is observed in several vascular disorders. 41,42 Phenotypic switching is characterized by downregulation of VSMC-contractile genes, such as myosin and SM α-actin, in exchange for a synthetic phenotype, characterized by non-VSMC-specific markers, reduced contractility, and heightened proliferation.…”

Section: Influence Of Bmpr2 Mutation On Metabolic Reprogramming Bmpr2...mentioning

confidence: 99%

“…42 Importantly, PTBP1 knockdown in these cells suppressed ILK-induced PASMC phenotypic switching and alleviated pulmonary vascular remodeling, 44 identifying a therapeutic benefit for normalization of PTBP1 signaling in PASMCs as well as ECs. Whether these effects are fueled by aberrant TGF-β signaling 40 warrants investigation.…”

Section: Influence Of Bmpr2 Mutation On Metabolic Reprogramming Bmpr2...mentioning

confidence: 99%

“…39 Heightened PKM2 expression and glycolytic activity are also observed in TGF-β–stimulated PASMCs isolated from rodent PAH models, via activation of the mTOR (mammalian target of rapamycin)/c-Myc (cellular myelocytomatosis oncogene)/PTBP1-hnRNPA1 (heterogenous nuclear ribonucleoprotein A1) pathway; however, its relationship to miR-124 expression and warrants confirmation. 40…”

Section: Influence Of Bmpr2 Mutation On Metabolic Reprogrammingmentioning

confidence: 99%

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BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension

Cuthbertson

Morrell

Caruso

2023

Circulation Research

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Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the BMPR2 gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.

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“…To acquire or lose proliferative and migratory potential and synthesize ECM, PASMCs can be reversibly converted from resting to contractile or synthetic in response to specific stimuli [ 59 ]. Multiple growth factors and inflammatory mediators, such as TGF-β, platelet-derived growth factor (PDGF), angiotensin-II; as well as stimuli, such as mechanical forces, epigenetics and ECM tissue heterogeneity, are essential regulators facilitating PASMCs transformed from the contractile to the synthetic phenotype [ 60 , 61 , 62 ]. PASMCs acquire migratory and proliferative capacities during this shift to achieve remodeling of the media membrane.…”

Section: Media Remodeling In Pulmonary Vascular Remodelingmentioning

confidence: 99%

Pulmonary Vascular Remodeling in Pulmonary Hypertension

Jia

Wang

Yan

et al. 2023

JPM

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Pulmonary vascular remodeling is the critical structural alteration and pathological feature in pulmonary hypertension (PH) and involves changes in the intima, media and adventitia. Pulmonary vascular remodeling consists of the proliferation and phenotypic transformation of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) of the middle membranous pulmonary artery, as well as complex interactions involving external layer pulmonary artery fibroblasts (PAFs) and extracellular matrix (ECM). Inflammatory mechanisms, apoptosis and other factors in the vascular wall are influenced by different mechanisms that likely act in concert to drive disease progression. This article reviews these pathological changes and highlights some pathogenetic mechanisms involved in the remodeling process.

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Platelet-Derived TGF (Transforming Growth Factor)-β1 Enhances the Aerobic Glycolysis of Pulmonary Arterial Smooth Muscle Cells by PKM2 (Pyruvate Kinase Muscle Isoform 2) Upregulation

Cited by 21 publications

References 47 publications

Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages

Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages

BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension

Pulmonary Vascular Remodeling in Pulmonary Hypertension

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