Metabolic control of smooth muscle cell phenotype switching in atherosclerosis

Zhang, R.-M.; Zhu, X.; Bae, H.; Zhang, J.; Li, Y.; Chen, P.-Y.; Shen, Y. H.; Tellides, G.; Snyder, N. W.; Jang, C.; Schwartz, M. A.; Arany, Z.; Simons, M.

doi:10.64898/2026.05.19.726223

bioRxiv · 10.64898/2026.05.19.726223

Metabolic control of smooth muscle cell phenotype switching in atherosclerosis

Zhang, R.-M.·Zhu, X.·Bae, H.·Zhang, J.·Li, Y.·Chen, P.-Y.·Shen, Y. H.·Tellides, G.·Snyder, N. W.·Jang, C.·Schwartz, M. A.·Arany, Z.·Simons, M.

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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 (TGF{beta}) signaling is among principal regulators of SMC contractility, we studied metabolic regulation of TGF{beta} signaling in SMCs in vitro and atherosclerotic mouse models and human lesions. We found that TGF{beta} induced Ac-CoA synthetase 2 (ACSS2)-dependent Ac-CoA production, by suppressing pyruvate dehydrogenase kinase 4 (PDK4). This stabilized R-SMADs and TGF{beta} receptor 1, preserving SMC contractile phenotype. SMC-specific PDK4 knockout mimicked the effect of TGF{beta} 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 TGF{beta} signaling, critical to the maintenance of the normal SMC contractile state and is regulated by PDK4 and carbohydrate metabolism. TeaserReducing PDK4 metabolically restricts aortic plaque growth via TGF{beta}-dependent SMC contractility.

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Zhang, R.-M., Zhu, X., Bae, H., Zhang, J., Li, Y., Chen, P.-Y., Shen, Y. H., Tellides, G., Snyder, N. W., Jang, C., Schwartz, M. A., Arany, Z., Simons, M.. 2026-05-21. Metabolic control of smooth muscle cell phenotype switching in atherosclerosis. https://doi.org/10.64898/2026.05.19.726223

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