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...

Full description

Saved in:
Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2024-12-01
Series:Pharmacological Research
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S1043661824004237
Tags: Add Tag
No Tags, Be the first to tag this record!
_version_ 1846117988619517952
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.
format Article
id doaj-art-8ca22da45ba24b6e961c7c33ebd74e00
institution Kabale University
issn 1096-1186
language English
publishDate 2024-12-01
publisher Elsevier
record_format Article
series Pharmacological Research
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
work_keys_str_mv AT mariolaolkowicz upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT agnieszkakaras upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT piotrberkowicz upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT patrycjakaczara upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT agnieszkajasztal upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT zuzannakurylowicz upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT filipfedak upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT hernandorosalessolano upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT kanchansinharoy upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT agnieszkakij upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT elzbietabuczek upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT januszpawliszyn upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice
AT stefanchlopicki upregulationofalox1212hetepathwayimpairsampkdependentmodulationofvascularmetabolisminapoeldlrmice