Pyruvate kinase M2 activation protects against the proliferation and migration of pulmonary artery smooth muscle cells

Zhang, Aikai; Yu, Fenfang; Yu, Wande; Ye, Peng; Liu, Pengfei; Gu, Yue; Chen, Shao‐Liang; Zhang, Hang

doi:10.1007/s00441-020-03245-2

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…When our study was in progress, 2 studies published this year showed that treating pulmonary artery SMC with PKM2 siRNA (small interfering RNA) reduces proliferation and migration, 29 and inhibiting PKM2 activity by inhibitor shikonin reduces oxidized low-density lipoprotein-induced SMC proliferation and migration in murine SMCs. 10 Although the recently published studies suggest a role of PKM2 in SMC proliferation and migration in vitro, in our opinion, the findings reported herein are definitive and novel for the following reasons.…”

Section: Discussionmentioning

confidence: 99%

Smooth Muscle Cell–Specific PKM2 (Pyruvate Kinase Muscle 2) Promotes Smooth Muscle Cell Phenotypic Switching and Neointimal Hyperplasia

Jain

Dhanesha

Doddapattar

et al. 2021

ATVB

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Objective: The role of glycolytic enzyme PKM (pyruvate kinase M) 2 in smooth muscle cell (SMC) phenotype switching and neointimal hyperplasia is poorly understood. We determined the role of PKM2 in SMC phenotype switching and neointimal hyperplasia. Approach and Results: We show that PKM2 is expressed in the SMC-rich neointima of the murine carotid artery and peri-strut areas in bare-metal stented human coronary arteries. PDGF-BB (platelet-derived growth factor-BB) stimulation upregulates the expression of PKM2 in cultured murine and human coronary SMC. To provide conclusive evidence for PKM2 in SMC function, we generated SMC-specific PKM2 −/− mutant strain. We report that PKM2 deletion in SMC reduces injury-induced neointimal hyperplasia by inhibiting SMC proliferation and migration, suppressing synthetic phenotype, and reducing aerobic glycolysis associated with decreased ERK (extracellular signal-regulated kinase), mTOR, and STAT3 (signal transducer and activator of transcription 3) signaling. Furthermore, we show that nuclear PKM2 interacts with STAT3 and β-catenin and regulates transcription of MEK5 (mitogen/extracellular signal-regulated kinase kinase-5), cyclin D1, GLUT1 (glucose transporter 1), and LDHA (lactate dehydrogenase A). Treatment of human coronary SMC with ML265, an activator that induces PKM2 tetramerization and blocks its nuclear translocation, inhibited proliferation, migration, and phenotypic switching. Perivascular application of PKM2 activator reduced neointimal hyperplasia in mice. Conclusions: These findings reveal that PKM2 is a key regulator of SMC function in vascular remodeling and implicates PKM2 as a potential target to reduce neointimal hyperplasia.

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Section: Discussionmentioning

confidence: 99%

Smooth Muscle Cell–Specific PKM2 (Pyruvate Kinase Muscle 2) Promotes Smooth Muscle Cell Phenotypic Switching and Neointimal Hyperplasia

Jain

Dhanesha

Doddapattar

et al. 2021

ATVB

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“…Our results suggest that during TEPP‐46‐mediated regulation of glycolysis, the transcriptional effect of PKM2 is stronger than its enzymatic activity. Phosphorylation of p‐PKM2 at the Y105 position can stabilize the conformation of PKM2 in the nucleus 43,44 . Therefore, Shikonin inhibits the levels of p‐PKM2 Y105 and nuclear entry of PKM2, where it can act as a transcriptional cofactor.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of p‐PKM2 at the Y105 position can stabilize the conformation of PKM2 in the nucleus. 43 , 44 Therefore, Shikonin inhibits the levels of p‐PKM2 Y105 and nuclear entry of PKM2, where it can act as a transcriptional cofactor. In our study, we indirectly proved the transcriptional regulation of PKM2 by detecting its nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

Chen,

Bai,

Chen

et al. 2023

Cell Proliferation

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We aimed to investigate the role of renal pericyte pyruvate kinase M2 (PKM2) in the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). The role of PKM2 in renal pericyte‐myofibroblast transdifferentiation was investigated in an AKI‐CKD mouse model. Platelet growth factor receptor beta (PDGFRβ)‐iCreERT2; tdTomato mice were used for renal pericyte tracing. Western blotting and immunofluorescence staining were used to examine protein expression. An 5‐ethynyl‐2′‐deoxyuridine assay was used to measure renal pericyte proliferation. A scratch cell migration assay was used to analyse cell migration. Seahorse experiments were used to examine glycolytic rates. Enzyme‐linked immunoassay was used to measure pyruvate kinase enzymatic activity and lactate concentrations. The PKM2 nuclear translocation inhibitors Shikonin and TEPP‐46 were used to alter pericyte transdifferentiation. In AKI‐CKD, renal pericytes proliferated and transdifferentiated into myofibroblasts and PKM2 is highly expressed in renal pericytes. Shikonin and TEPP‐46 inhibited pericyte proliferation, migration, and pericyte‐myofibroblast transdifferentiation by reducing nuclear PKM2 entry. In the nucleus, PKM2 promoted downstream lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) transcription, which are critical for glycolysis. Therefore, PKM2 regulates pericyte glycolytic and lactate production, which regulates renal pericyte‐myofibroblast transdifferentiation. PKM2‐regulated renal pericyte‐myofibroblast transdifferentiation by regulating downstream LDHA and GLUT1 transcription and lactate production. Reducing nuclear PKM2 import can reduce renal pericytes‐myofibroblasts transdifferentiation, providing new ideas for AKI‐CKD treatment.

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“…Tepp-46 (ML-265) is a selective pyruvate kinase M2 (PKM2) tetramer stabilizer [ 33 ]. Transfected BEAS-2B cells were treated with 10 nM of Tepp-46 (purchased from VWR, Radnor, PA, USA) for four hours before downstream assays and measurements were conducted.…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE

Allen

Santerre

Arjona

et al. 2022

Viruses

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Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.

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Pyruvate kinase M2 activation protects against the proliferation and migration of pulmonary artery smooth muscle cells

Cited by 8 publications

References 35 publications

Smooth Muscle Cell–Specific PKM2 (Pyruvate Kinase Muscle 2) Promotes Smooth Muscle Cell Phenotypic Switching and Neointimal Hyperplasia

Smooth Muscle Cell–Specific PKM2 (Pyruvate Kinase Muscle 2) Promotes Smooth Muscle Cell Phenotypic Switching and Neointimal Hyperplasia

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE

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