Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice
Mitochondrial dysfunction and 12-lipoxygenase (ALOX12)-derived 12(S)-HETE production have been associated with vascular inflammation and the pathogenesis of atherosclerosis. However, the role of ALOX12 in regulating vascular energy metabolism in vascular inflammation has not been studied to date. Us...
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Elsevier
2024-12-01
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Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004237 |
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author | Mariola Olkowicz Agnieszka Karas Piotr Berkowicz Patrycja Kaczara Agnieszka Jasztal Zuzanna Kurylowicz Filip Fedak Hernando Rosales-Solano Kanchan Sinha Roy Agnieszka Kij Elzbieta Buczek Janusz Pawliszyn Stefan Chlopicki |
author_facet | Mariola Olkowicz Agnieszka Karas Piotr Berkowicz Patrycja Kaczara Agnieszka Jasztal Zuzanna Kurylowicz Filip Fedak Hernando Rosales-Solano Kanchan Sinha Roy Agnieszka Kij Elzbieta Buczek Janusz Pawliszyn Stefan Chlopicki |
author_sort | Mariola Olkowicz |
collection | DOAJ |
description | Mitochondrial dysfunction and 12-lipoxygenase (ALOX12)-derived 12(S)-HETE production have been associated with vascular inflammation and the pathogenesis of atherosclerosis. However, the role of ALOX12 in regulating vascular energy metabolism in vascular inflammation has not been studied to date. Using mitochondrial and glycolysis functional profiling with the Seahorse extracellular flux analyzer, metabolipidomics, and proteomic analysis (LC-MS/MS), we characterized alterations in vascular energy metabolism in 2- and 6-month-old ApoE/LDLR−/− vs. control C57BL/6 mice. We identified that aorta of 6-month-old ApoE/LDLR−/− mice displayed compromised mitochondrial metabolism manifested by the reduced expression of mitochondrial enzymes, impaired mitochondrial respiration, and consequently diminished respiratory reserve capacity. An increased flux through the glycolysis/lactate shuttle, the hexosamine biosynthetic pathway (HBP), and the pentose phosphate pathway (PPP) was also recognized. Interestingly, ALOX12−12-HETE was the most upregulated axis in eicosanoid metabolism and histological examinations indicated that ApoE/LDLR−/− mice showed increased aortic expression of ALOX12, particularly in early atherosclerotic plaque areas. Remarkably, the joint blocking of ALOX12 and activation of AMPK, but not AMPK activation alone, resulted in the reprogramming of vascular metabolism, with improved mitochondrial respiration and suppressed auxiliary pathways (HBP, PPP, itaconate shunt). In conclusion, excessive activation of the ALOX12–12-HETE pathway in vascular inflammation in early atherosclerosis inhibits AMPK-dependent regulation of vascular metabolism. Consequently, ALOX12 may represent a novel target to boost impaired vascular mitochondrial function in pro-atherosclerotic vascular inflammation. |
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id | doaj-art-8ca22da45ba24b6e961c7c33ebd74e00 |
institution | Kabale University |
issn | 1096-1186 |
language | English |
publishDate | 2024-12-01 |
publisher | Elsevier |
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spelling | doaj-art-8ca22da45ba24b6e961c7c33ebd74e002024-12-18T08:47:14ZengElsevierPharmacological Research1096-11862024-12-01210107478Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− miceMariola Olkowicz0Agnieszka Karas1Piotr Berkowicz2Patrycja Kaczara3Agnieszka Jasztal4Zuzanna Kurylowicz5Filip Fedak6Hernando Rosales-Solano7Kanchan Sinha Roy8Agnieszka Kij9Elzbieta Buczek10Janusz Pawliszyn11Stefan Chlopicki12Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Corresponding author.Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Lojasiewicza 11, Krakow 30-348, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Lojasiewicza 11, Krakow 30-348, PolandDepartment of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, CanadaDepartment of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, CanadaJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, PolandJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Lojasiewicza 11, Krakow 30-348, PolandDepartment of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, CanadaJagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Krakow 30-348, Poland; Department of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow 31-531, PolandMitochondrial dysfunction and 12-lipoxygenase (ALOX12)-derived 12(S)-HETE production have been associated with vascular inflammation and the pathogenesis of atherosclerosis. However, the role of ALOX12 in regulating vascular energy metabolism in vascular inflammation has not been studied to date. Using mitochondrial and glycolysis functional profiling with the Seahorse extracellular flux analyzer, metabolipidomics, and proteomic analysis (LC-MS/MS), we characterized alterations in vascular energy metabolism in 2- and 6-month-old ApoE/LDLR−/− vs. control C57BL/6 mice. We identified that aorta of 6-month-old ApoE/LDLR−/− mice displayed compromised mitochondrial metabolism manifested by the reduced expression of mitochondrial enzymes, impaired mitochondrial respiration, and consequently diminished respiratory reserve capacity. An increased flux through the glycolysis/lactate shuttle, the hexosamine biosynthetic pathway (HBP), and the pentose phosphate pathway (PPP) was also recognized. Interestingly, ALOX12−12-HETE was the most upregulated axis in eicosanoid metabolism and histological examinations indicated that ApoE/LDLR−/− mice showed increased aortic expression of ALOX12, particularly in early atherosclerotic plaque areas. Remarkably, the joint blocking of ALOX12 and activation of AMPK, but not AMPK activation alone, resulted in the reprogramming of vascular metabolism, with improved mitochondrial respiration and suppressed auxiliary pathways (HBP, PPP, itaconate shunt). In conclusion, excessive activation of the ALOX12–12-HETE pathway in vascular inflammation in early atherosclerosis inhibits AMPK-dependent regulation of vascular metabolism. Consequently, ALOX12 may represent a novel target to boost impaired vascular mitochondrial function in pro-atherosclerotic vascular inflammation.http://www.sciencedirect.com/science/article/pii/S104366182400423712-lipoxygenaseVascular energy metabolismAMP-activated protein kinase (AMPK)Mitochondrial respirationVascular inflammationAtherosclerosis |
spellingShingle | Mariola Olkowicz Agnieszka Karas Piotr Berkowicz Patrycja Kaczara Agnieszka Jasztal Zuzanna Kurylowicz Filip Fedak Hernando Rosales-Solano Kanchan Sinha Roy Agnieszka Kij Elzbieta Buczek Janusz Pawliszyn Stefan Chlopicki Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice Pharmacological Research 12-lipoxygenase Vascular energy metabolism AMP-activated protein kinase (AMPK) Mitochondrial respiration Vascular inflammation Atherosclerosis |
title | Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice |
title_full | Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice |
title_fullStr | Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice |
title_full_unstemmed | Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice |
title_short | Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice |
title_sort | upregulation of alox12 12 hete pathway impairs ampk dependent modulation of vascular metabolism in apoe ldlr mice |
topic | 12-lipoxygenase Vascular energy metabolism AMP-activated protein kinase (AMPK) Mitochondrial respiration Vascular inflammation Atherosclerosis |
url | http://www.sciencedirect.com/science/article/pii/S1043661824004237 |
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