Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis

Zhang, Hui; Wang, Daren; Li, Min; Plecitá–Hlavatá, Lydie; D’Alessandro, Angelo; Tauber, Jan; Riddle, Suzette; Kumar, Sushil; Flockton, Amanda; McKeon, B. Alexandre; Frid, Maria G.; Reisz, Julie A.; Caruso, Paola; Kasmi, Karim C. El; Ježek, Petr; Morrell, Nicholas W.; Hu, Chengjun; Stenmark, Kurt R.

doi:10.1161/circulationaha.117.028069

Cited by 190 publications

(207 citation statements)

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“…42 Defined by its location, the vascular adventitial layer is made up of multiple mesenchymal cell types, predominantly fibroblasts. 19 Also, adventitial fibroblasts are well-documented to transdifferentiate into myofibroblasts identified by expression of the contractile protein α-smooth muscle actin. 43 Like interstitial fibroblasts, adventitial fibroblasts are known for their action on extracellular matrix protein deposition and secretion of inflammatory cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

“…We attempted to identify the influence of tissue pressure overload on TG2 expression and activity in LVs of the TAC experimental mouse model. 19,20 In the current study, we investigated the effects of hyperglycemia and aerobic glycolysis on TG2 and fibroblast cell signaling and function. 15 Glycolysis is stimulated by hypoxia and is also upregulated in the presence of oxygen as in tumor biology where it has been referred to as the Warburg effect (aerobic glycolysis).…”

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confidence: 99%

“…16 Glycolysis is a multiple step metabolic process in response to glucose uptake 17,18 in which enzymatically catalyzed steps convert glucose to pyruvate molecules for cellular energy generation. 19,21,27 However, downstream signal transduction pathways of glycolysis-mediated effects are not well-defined. 19,20 In the current study, we investigated the effects of hyperglycemia and aerobic glycolysis on TG2 and fibroblast cell signaling and function.…”

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confidence: 99%

“…In fact, the glycolytic pathway has recently been shown to be associated with the fibrogenic phenotype. 19,20 In the current study, we investigated the effects of hyperglycemia and aerobic glycolysis on TG2 and fibroblast cell signaling and function. Since the terminal glycolytic enzyme pyruvate kinase muscle isoform 2 (PKM2) has been reported to mediate metabolic and inflammatory dysfunction in cardiovascular disease, 21 we specifically selected this enzyme for some of our studies.…”

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confidence: 99%

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Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

et al. 2019

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The pathophysiology of pulmonary hypertension (PH) and heart failure (HF) includes fibrogenic remodeling associated with the loss of pulmonary arterial (PA) and cardiac compliance. We and others have previously identified transglutaminase 2 (TG2) as a participant in adverse fibrogenic remodeling. However, little is known about the biologic mechanisms that regulate TG2 function. We examined physiological mouse models of experimental PH, HF, and type 1 diabetes that are associated with altered glucose metabolism/glycolysis and report here that TG2 expression and activity are elevated in pulmonary and cardiac tissues under all these conditions. We additionally used PA adventitial fibroblasts to test the hypothesis that TG2 is an intermediary between enhanced tissue glycolysis and fibrogenesis. Our in vitro results show that glycolytic enzymes and TG2 are upregulated in fibroblasts exposed to high glucose, which stimulates cellular glycolysis as measured by Seahorse analysis. We examined the relationship of TG2 to a terminal glycolytic enzyme, pyruvate kinase M2 (PKM2), and found that PKM2 regulates glucose‐induced TG2 expression and activity as well as fibrogenesis. Our studies further show that TG2 inhibition blocks glucose‐induced fibrogenesis and cell proliferation. Our findings support a novel role for glycolysis‐mediated TG2 induction and tissue fibrosis associated with experimental PH, HF, and hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

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Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

et al. 2019

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“…Recently, metabolomics has demonstrated its usage in understanding fundamental insights into molecular mechanisms of neuropsychiatric diseases, cardiovascular diseases, and cancer. 14,15,55 Particularly, a complementary approach integrating both discovery metabolomics and metabolic flux analysis involving stable-isotope labeling was shown to provide significant biological insights into cancer metabolism. 56 Using both metabolomics and metabolic flux analysis, Jia et al 57 reported that AML was prone to SLC2A5-mediated fructose utilization to offset glucose insufficiency.…”

Section: Understanding Mechanisms Of Diseasesmentioning

confidence: 99%

Emerging Applications of Metabolomics in Clinical Pharmacology

Pang

Wang

2019

Clin Pharma and Therapeutics

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Metabolic disturbances have been associated with many human diseases, including cancer, diabetes, and cardiovascular disease. Metabolomics, a rapidly growing member of the –omics family, investigates cellular metabolism by quantifying metabolites on a large scale and provides a link between metabolic pathways and the upstream genome that governs them. With the advances in analytical technologies, metabolomics is becoming a powerful tool for identifying diagnostic biomarkers of diseases, elucidating the pathological mechanisms, discovering novel drug targets, predicting drug responses, interpreting the mechanisms of drug action, as well as enabling precision treatment of patients. In this review, we highlight the recent advances of technologies and methodologies in metabolomics and their applications to the field of clinical pharmacology. Recent publications from 2013 to 2018 are covered in the review, and current challenges and potential future directions in the field are also discussed.

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Fe(III)‐Shikonin Supramolecular Nanomedicine for Combined Therapy of Tumor via Ferroptosis and Necroptosis

Feng

Shi

Liu

et al. 2021

Adv Healthcare Materials

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Most of the antitumor chemotherapeutic drugs execute the therapeutic performance upon eliciting tumor cell apoptosis, which may cause chemoresistance of tumors. Design of novel drugs to eradicate apoptosis-resistant tumors via non-apoptotic cell death pathways is promising for improving the long-term chemotherapeutic efficacy. Herein, a Fe(III)-Shikonin metal-polyphenol-coordinated supramolecular nanomedicine for combined therapy of tumor via ferroptosis and necroptosis is designed. The construction of the nanomedicine based on the coordinated self-assembly between Fe 3+ and Shikonin not only overcomes the shortcomings of Shikonin including its low bioavailability and high toxicity toward normal tissues, but also integrates the theranostics functions of Fe ions. Under the exposure of the high concentration of glutathione (GSH) in tumor cells, the as-prepared nanomedicine will disassemble into Fe 2+ and Shikonin, followed by stimulating the tumor cell death through ferroptosis and necroptosis. In addition, benefiting from the stealth effect of polyethylene glycol (PEG) and the targeting ability of cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) to 𝜶 v 𝜷 3 -integrin, NH 2 -PEG-cRGD-modified nanomedicine exhibits a GSH-responsive therapy toward 4T1 tumor in vivo and self-enhanced longitudinal relaxation (T 1 )-weighted imaging property. Since the self-assembly of natural Shikonin and human body-necessary Fe element is facile and feasible, the work may provide a promising supramolecular nanomedicine for next-generation chemotherapeutic applications.

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Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis

Cited by 190 publications

References 50 publications

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

Emerging Applications of Metabolomics in Clinical Pharmacology

Fe(III)‐Shikonin Supramolecular Nanomedicine for Combined Therapy of Tumor via Ferroptosis and Necroptosis

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