Preprint
Metabolic control of smooth muscle cell phenotype switching in atherosclerosis
bioRxiv
Cold Spring Harbor Laboratory, 1.1
05/21/2026
DOI: 10.64898/2026.05.19.726223
PMID: 42239337
Abstract
The loss of smooth muscle cell (SMC) contractile phenotype contributes to various diseases including atherosclerosis. However, its metabolic basis is not entirely elucidated. Since the transforming growth factor beta (TGFβ) signaling is among principal regulators of SMC contractility, we studied metabolic regulation of TGFβ signaling in SMCs in vitro and atherosclerotic mouse models and human lesions. We found that TGFβ induced Ac-CoA synthetase 2 (ACSS2)-dependent Ac-CoA production, by suppressing pyruvate dehydrogenase kinase 4 (PDK4). This stabilized R-SMADs and TGFβ receptor 1, preserving SMC contractile phenotype. SMC-specific PDK4 knockout mimicked the effect of TGFβ signaling both metabolically and phenotypically, increasing glucose-derived synthesis of Ac-CoA and SMC contractile phenotype. SMC-specific Pdk4 knockout in ApoE knockout mice reduced atherosclerosis. Furthermore, human specimens demonstrated a strong correlation between PDK4 level and atherosclerosis severity. These findings indicate that continuous TGFβ signaling, critical to the maintenance of the normal SMC contractile state and is regulated by PDK4 and carbohydrate metabolism.
Reducing PDK4 metabolically restricts aortic plaque growth via TGFβ-dependent SMC contractility.
Details
- Title: Subtitle
- Metabolic control of smooth muscle cell phenotype switching in atherosclerosis
- Creators
- Rong-Mo Zhang - Yale UniversityXiaolong Zhu - Yale UniversityHosung Bae - University of California, IrvineJiasheng Zhang - Yale UniversityYanming Li - Baylor College of MedicinePei-Yu Chen - Yale UniversityYing H. Shen - Baylor College of MedicineGeorge Tellides - Yale UniversityNathaniel Snyder - Temple UniversityCholsoon Jang - University of California, IrvineMartin A. Schwartz - Yale UniversityZoltan Arany - University of PennsylvaniaMichael Simons - Yale University
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- Edition
- 1.1
- DOI
- 10.64898/2026.05.19.726223
- PMID
- 42239337
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory
- Number of pages
- 72
- Language
- English
- Date posted
- 05/21/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217009802771
Metrics
3 Record Views