Journal article
Smooth Muscle Cell-Specific PKM2 (Pyruvate Kinase Muscle 2) Promotes Smooth Muscle Cell Phenotypic Switching and Neointimal Hyperplasia
Arteriosclerosis, thrombosis, and vascular biology, Vol.41(5), pp.1724-1737
05/05/2021
DOI: 10.1161/ATVBAHA.121.316021
PMCID: PMC8062279
PMID: 33691477
Abstract
Objective:
The role of glycolytic enzyme PKM2 (pyruvate kinase muscle 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 (mammalian target of rapamycin), and STAT3 (signal transducer and activator of transcription 3) signaling. Furthermore, we show that nuclear PKM2 interacts with STAT3 and beta-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.
Details
- Title: Subtitle
- Smooth Muscle Cell-Specific PKM2 (Pyruvate Kinase Muscle 2) Promotes Smooth Muscle Cell Phenotypic Switching and Neointimal Hyperplasia
- Creators
- Manish Jain - University of IowaNirav Dhanesha - University of IowaPrakash Doddapattar - University of IowaManasa K. Nayak - University of IowaLiang Guo - CVPath InstituteAnne Cornelissen - CVPath InstituteSteven R. Lentz - University of IowaAloke V. Finn - CVPath InstituteAnil K. Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.41(5), pp.1724-1737
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/ATVBAHA.121.316021
- PMID
- 33691477
- PMCID
- PMC8062279
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Number of pages
- 14
- Grant note
- 18CVD02 / CVPath Institute, Leducq Foundation Transatlantic Networks of Excellence Grant 18EIA33900009 / American Heart Association R35HL139926; R01NS109910; U01NS113388 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 05/05/2021
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359566902771
Metrics
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