Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk
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Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk. / Forteza, Maria J; Berg, Martin; Edsfeldt, Andreas; Sun, Jangming; Baumgartner, Roland; Kareinen, Ilona; Casagrande, Felipe Beccaria; Hedin, Ulf; Zhang, Song; Vuckovic, Ivan; Dzeja, Petras P; Polyzos, Konstantinos A; Gisterå, Anton; Trauelsen, Mette; Schwartz, Thue W; Dib, Lea; Herrmann, Joerg; Monaco, Claudia; Matic, Ljubica; Gonçalves, Isabel; Ketelhuth, Daniel F J.
In: Cardiovascular Research, Vol. 119, No. 7, 2023, p. 1524-1536.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023
Y1 - 2023
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 major metabolic step regulating inflammation. Whether the PDK/PDH axis plays role in vascular inflammation and atherosclerotic cardiovascular disease has never been studied.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 major metabolic step regulating inflammation. Whether the PDK/PDH axis plays role in vascular inflammation and atherosclerotic cardiovascular disease has never been studied.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.
U2 - 10.1093/cvr/cvad038
DO - 10.1093/cvr/cvad038
M3 - Journal article
C2 - 36866436
VL - 119
SP - 1524
EP - 1536
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 7
ER -
ID: 342681520