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Pyruvate dehydrogen...
Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk
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- Forteza, Maria J. (author)
- Karolinska Institutet,Karolinska University Hospital
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- Berg, Martin (author)
- Karolinska University Hospital
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- Edsfeldt, Andreas (author)
- Lund University,Lunds universitet,Kardiovaskulär forskning - translationella studier,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,Cardiovascular Research - Translational Studies,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,Skåne University Hospital
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- Sun, Jangming (author)
- Lund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Kardiovaskulär forskning - translationella studier,Diabetes - Molecular Metabolism,Lund University Research Groups,Cardiovascular Research - Translational Studies,Skåne University Hospital
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- Baumgartner, Roland (author)
- Karolinska University Hospital
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- Kareinen, Ilona (author)
- Karolinska University Hospital
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- Casagrande, Felipe Beccaria (author)
- Karolinska Institutet,Karolinska University Hospital
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- Hedin, Ulf (author)
- Karolinska Institutet,Karolinska University Hospital
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- Zhang, Song (author)
- Mayo Clinic Minnesota
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- Vuckovic, Ivan (author)
- Mayo Clinic Minnesota
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- Dzeja, Petras P. (author)
- Mayo Clinic Minnesota
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- Polyzos, Konstantinos A. (author)
- Karolinska University Hospital
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- Gisterå, Anton (author)
- Karolinska Institutet,Karolinska University Hospital
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- Trauelsen, Mette (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research
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- Schwartz, Thue W. (author)
- Novo Nordisk Foundation Centre for Basic Metabolic Research
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- Dib, Lea (author)
- Kennedy Institute of Rheumatology
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- Herrmann, Joerg (author)
- Mayo Clinic Minnesota
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- Monaco, Claudia (author)
- Kennedy Institute of Rheumatology
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- Matic, Ljubica (author)
- Karolinska Institutet,Karolinska University Hospital
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- Gonçalves, Isabel (author)
- Lund University,Lunds universitet,Kardiovaskulär forskning - translationella studier,Forskargrupper vid Lunds universitet,Cardiovascular Research - Translational Studies,Lund University Research Groups,Skåne University Hospital
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- Ketelhuth, Daniel F.J. (author)
- Karolinska Institutet,Karolinska University Hospital,University of Southern Denmark
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(creator_code:org_t)
- 2023-03-02
- 2023
- English 13 s.
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:7, s. 1524-1536
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- atherosclerosis
- CVD
- immunometabolism
- inflammation
- PDK
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Forteza, Maria J ...
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Berg, Martin
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Edsfeldt, Andrea ...
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Sun, Jangming
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Baumgartner, Rol ...
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Kareinen, Ilona
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show more...
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Casagrande, Feli ...
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Hedin, Ulf
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Zhang, Song
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Vuckovic, Ivan
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Dzeja, Petras P.
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Polyzos, Konstan ...
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Gisterå, Anton
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Trauelsen, Mette
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Schwartz, Thue W ...
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Dib, Lea
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Herrmann, Joerg
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Monaco, Claudia
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Matic, Ljubica
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Gonçalves, Isabe ...
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Ketelhuth, Danie ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Cardiovascular R ...
- By the university
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Lund University
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Karolinska Institutet