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Updated: Jun 5, 2026
Isolation of Primary Patient-specific Aortic Smooth Muscle Cells and Semiquantitative Real-time Contraction Measurements In Vitro
Published on: February 15, 2022
Metabolic control of smooth muscle cell phenotype switching in atherosclerosis
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.
Teaser:
Reducing PDK4 metabolically restricts aortic plaque growth via TGFβ-dependent SMC contractility.
Insights
Pyruvate dehydrogenase kinase 4 (PDK4) regulates smooth muscle cell (SMC) contractility and atherosclerosis by controlling metabolism. Reducing PDK4 preserves SMC phenotype and restricts plaque growth.
Area of Science:
- Biochemistry
- Cell Biology
- Cardiovascular Research
Background:
- Loss of smooth muscle cell (SMC) contractile phenotype is implicated in diseases like atherosclerosis.
- The metabolic underpinnings of SMC phenotype regulation are not fully understood.
- Transforming growth factor beta (TGFβ) signaling is a key regulator of SMC contractility.
Purpose of the Study:
- To investigate the metabolic regulation of TGFβ signaling in SMCs.
- To elucidate the role of pyruvate dehydrogenase kinase 4 (PDK4) in SMC phenotype and atherosclerosis.
- To determine the impact of PDK4 on TGFβ signaling and Ac-CoA production.
Main Methods:
- Studied TGFβ signaling and metabolism in SMCs in vitro.
- Utilized SMC-specific PDK4 knockout mouse models.
- Analyzed atherosclerotic mouse models (ApoE knockout) and human atherosclerotic lesions.
Main Results:
- TGFβ signaling induces Ac-CoA synthetase 2 (ACSS2)-dependent Ac-CoA production by suppressing PDK4, stabilizing R-SMADs and TGFβ receptor 1, thus preserving SMC contractile phenotype.
- SMC-specific PDK4 knockout mimicked TGFβ effects, increasing glucose-derived Ac-CoA synthesis and SMC contractile phenotype.
- SMC-specific Pdk4 knockout in ApoE knockout mice reduced atherosclerosis.
- Human specimens showed a strong correlation between PDK4 levels and atherosclerosis severity.
Conclusions:
- Continuous TGFβ signaling is critical for maintaining SMC contractile state.
- PDK4 and carbohydrate metabolism regulate TGFβ signaling and SMC phenotype.
- Metabolically restricting PDK4 limits aortic plaque growth via TGFβ-dependent SMC contractility.
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