Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk

Maria J. Forteza; Martin Berg; Andreas Edsfeldt; Jangming Sun; Roland Baumgartner; Ilona Kareinen; Felipe Beccaria Casagrande; Ulf Hedin; Song Zhang; Ivan Vuckovic; Petras P. Dzeja; Konstantinos A. Polyzos; Anton Gisterå; Mette Trauelsen; Thue W. Schwartz; Lea Dib; Joerg Herrmann; Claudia Monaco; Ljubica Matic; Isabel Gonçalves; Daniel F.J. Ketelhuth

doi:10.1093/cvr/cvad038

Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk

Maria J. Forteza, Martin Berg, Andreas Edsfeldt, Jangming Sun, Roland Baumgartner, Ilona Kareinen, Felipe Beccaria Casagrande, Ulf Hedin, Song Zhang, Ivan Vuckovic, Petras P. Dzeja, Konstantinos A. Polyzos, Anton Gisterå, Mette Trauelsen, Thue W. Schwartz, Lea Dib, Joerg Herrmann, Claudia Monaco, Ljubica Matic, Isabel GonçalvesDaniel F.J. Ketelhuth

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.

Original language	English (US)
Pages (from-to)	1524-1536
Number of pages	13
Journal	Cardiovascular research
Volume	119
Issue number	7
DOIs	https://doi.org/10.1093/cvr/cvad038
State	Published - Jun 1 2023

Keywords

CVD
PDK
atherosclerosis
immunometabolism
inflammation

ASJC Scopus subject areas

General Medicine

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10.1093/cvr/cvad038

Cite this

Forteza, M. J., Berg, M., Edsfeldt, A., Sun, J., Baumgartner, R., Kareinen, I., Casagrande, F. B., Hedin, U., Zhang, S., Vuckovic, I., Dzeja, P. P., Polyzos, K. A., Gisterå, A., Trauelsen, M., Schwartz, T. W., Dib, L., Herrmann, J., Monaco, C., Matic, L., ... Ketelhuth, D. F. J. (2023). Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk. Cardiovascular research, 119(7), 1524-1536. https://doi.org/10.1093/cvr/cvad038

Forteza, MJ, Berg, M, Edsfeldt, A, Sun, J, Baumgartner, R, Kareinen, I, Casagrande, FB, Hedin, U, Zhang, S, Vuckovic, I, Dzeja, PP, Polyzos, KA, Gisterå, A, Trauelsen, M, Schwartz, TW, Dib, L, Herrmann, J, Monaco, C, Matic, L, Gonçalves, I & Ketelhuth, DFJ 2023, 'Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk', Cardiovascular research, vol. 119, no. 7, pp. 1524-1536. https://doi.org/10.1093/cvr/cvad038

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title = "Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk",

abstract = "Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.",

keywords = "CVD, PDK, atherosclerosis, immunometabolism, inflammation",

author = "Forteza, {Maria J.} and Martin Berg and Andreas Edsfeldt and Jangming Sun and Roland Baumgartner and Ilona Kareinen and Casagrande, {Felipe Beccaria} and Ulf Hedin and Song Zhang and Ivan Vuckovic and Dzeja, {Petras P.} and Polyzos, {Konstantinos A.} and Anton Gister{\aa} and Mette Trauelsen and Schwartz, {Thue W.} and Lea Dib and Joerg Herrmann and Claudia Monaco and Ljubica Matic and Isabel Gon{\c c}alves and Ketelhuth, {Daniel F.J.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2023",

month = jun,

day = "1",

doi = "10.1093/cvr/cvad038",

language = "English (US)",

volume = "119",

pages = "1524--1536",

journal = "Cardiovascular research",

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TY - JOUR

T1 - Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk

AU - Forteza, Maria J.

AU - Berg, Martin

AU - Edsfeldt, Andreas

AU - Sun, Jangming

AU - Baumgartner, Roland

AU - Kareinen, Ilona

AU - Casagrande, Felipe Beccaria

AU - Hedin, Ulf

AU - Zhang, Song

AU - Vuckovic, Ivan

AU - Dzeja, Petras P.

AU - Polyzos, Konstantinos A.

AU - Gisterå, Anton

AU - Trauelsen, Mette

AU - Schwartz, Thue W.

AU - Dib, Lea

AU - Herrmann, Joerg

AU - Monaco, Claudia

AU - Matic, Ljubica

AU - Gonçalves, Isabel

AU - Ketelhuth, Daniel F.J.

PY - 2023/6/1

Y1 - 2023/6/1

N2 - Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.

AB - Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.

KW - CVD

KW - PDK

KW - atherosclerosis

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KW - inflammation

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Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk

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Keywords

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