Authors
Rong-Mo Zhang, Xiaolong Zhu, Hosung Bae, Jiasheng Zhang, Yanming Li, Pei-Yu Chen, Ying H Shen, George Tellides, Nathaniel Snyder, Cholsoon Jang, Martin A Schwartz, Zoltan Arany, Michael Simons
Published in
Science advances. Volume 12. Issue 35. Pages eaef6065. Aug 28, 2026. Epub Aug 26, 2026.
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 SMC TGFβ signaling, critical to the maintenance of the normal SMC contractile state, is regulated by PDK4 and carbohydrate metabolism.
PMID:
42647644
Bibliographic data and abstract were imported from PubMed on 27 Aug 2026.
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