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

Forteza, Maria J. ; Berg, Martin ; Edsfeldt, Andreas LU ; Sun, Jangming LU orcid ; Baumgartner, Roland ; Kareinen, Ilona ; Casagrande, Felipe Beccaria ; Hedin, Ulf ; Zhang, Song and Vuckovic, Ivan , et al. (2023) In Cardiovascular Research 119(7). p.1524-1536
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atherosclerosis, CVD, immunometabolism, inflammation, PDK
in
Cardiovascular Research
volume
119
issue
7
pages
13 pages
publisher
Oxford University Press
external identifiers
  • pmid:36866436
  • scopus:85165911357
ISSN
0008-6363
DOI
10.1093/cvr/cvad038
language
English
LU publication?
yes
id
3fe9a3e8-0b8b-407f-b92b-afb1ecb15983
date added to LUP
2023-11-06 13:03:50
date last changed
2024-04-19 03:39:55
@article{3fe9a3e8-0b8b-407f-b92b-afb1ecb15983,
  abstract     = {{<p>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.</p>}},
  author       = {{Forteza, Maria J. and Berg, Martin and Edsfeldt, Andreas and Sun, Jangming and Baumgartner, Roland and Kareinen, Ilona and Casagrande, Felipe Beccaria and Hedin, Ulf and Zhang, Song and Vuckovic, Ivan and Dzeja, Petras P. and Polyzos, Konstantinos A. and Gisterå, Anton and Trauelsen, Mette and Schwartz, Thue W. and Dib, Lea and Herrmann, Joerg and Monaco, Claudia and Matic, Ljubica and Gonçalves, Isabel and Ketelhuth, Daniel F.J.}},
  issn         = {{0008-6363}},
  keywords     = {{atherosclerosis; CVD; immunometabolism; inflammation; PDK}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1524--1536}},
  publisher    = {{Oxford University Press}},
  series       = {{Cardiovascular Research}},
  title        = {{Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk}},
  url          = {{http://dx.doi.org/10.1093/cvr/cvad038}},
  doi          = {{10.1093/cvr/cvad038}},
  volume       = {{119}},
  year         = {{2023}},
}