Min Wan1, Xiang Hua2, Jun Su3, Divya Thiagarajan3, Anna G Frostegård3, Jesper Z Haeggström1, Johan Frostegård4. 1. Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 2. IMM, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Divisions of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Insitutet, Stockholm, Sweden. Electronic address: xiang.hua@ki.se. 3. IMM, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 4. IMM, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Divisions of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Insitutet, Stockholm, Sweden; Acute Internal Medicine, Karolinska University Hospital, Huddinge, Sweden.
Abstract
OBJECTIVE: Cardiolipin (CL) is a phospholipid with an unusual dimeric structure containing four double-bonds and is easily oxidized. CL is present in mitochondria. Here we explored potential pro-inflammatory properties implicated in cardiovascular disease (CVD): activation of endothelial cells, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4), by oxidized CL (oxCL) and inhibitory effects of Annexin A5, an antithrombotic and antiinflammatory plasma protein. METHODS: In monocytes/macrophages and neutrophils, calcium mobilization was monitored spectrophotometrically with Fura-2 and synthesis of LTB4 was analyzed by EIA. Expression of adhesion molecules on endothelial cells was studied by FACScan. Binding of Annexin A5 were analyzed by ELISA. The mRNA expression of 5-LOX and cyclooxygenase-2 was assessed by Real-Time PCR. RESULTS: We demonstrate that oxCL but not its non-oxidized counterpart CL induces biosynthesis of LTB4 and increases intracellular concentrations of calcium in monocytes/macrophages and neutrophils. oxCL rather than CL selectively elevates gene expression of 5-LOX but not COX-2 in human macrophages. Furthermore, oxCL but not CL raises levels of adhesion molecules ICAM-1 and VCAM-1 in endothelial cells. Annexin A5 can bind oxCL to abolish all these oxCL-induced effects. CONCLUSIONS: oxCL may promote inflammation and related diseases especially in conditions involving unresolved apoptosis and necrosis, such as atherosclerosis, where free oxCL is likely to be released from liberated mitochondria. Increased intracellular calcium could activate 5-LOX to produce Leukotriene B4 (LTB4). Annexin A5 inhibits the pro-inflammatory effects of oxCL and its potential therapeutic use when oxCL is implicated in inflammation could be of interest.
OBJECTIVE: Cardiolipin (CL) is a phospholipid with an unusual dimeric structure containing four double-bonds and is easily oxidized. CL is present in mitochondria. Here we explored potential pro-inflammatory properties implicated in cardiovascular disease (CVD): activation of endothelial cells, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4), by oxidized CL (oxCL) and inhibitory effects of Annexin A5, an antithrombotic and antiinflammatory plasma protein. METHODS: In monocytes/macrophages and neutrophils, calcium mobilization was monitored spectrophotometrically with Fura-2 and synthesis of LTB4 was analyzed by EIA. Expression of adhesion molecules on endothelial cells was studied by FACScan. Binding of Annexin A5 were analyzed by ELISA. The mRNA expression of 5-LOX and cyclooxygenase-2 was assessed by Real-Time PCR. RESULTS: We demonstrate that oxCL but not its non-oxidized counterpart CL induces biosynthesis of LTB4 and increases intracellular concentrations of calcium in monocytes/macrophages and neutrophils. oxCL rather than CL selectively elevates gene expression of 5-LOX but not COX-2 in human macrophages. Furthermore, oxCL but not CL raises levels of adhesion molecules ICAM-1 and VCAM-1 in endothelial cells. Annexin A5 can bind oxCL to abolish all these oxCL-induced effects. CONCLUSIONS:oxCL may promote inflammation and related diseases especially in conditions involving unresolved apoptosis and necrosis, such as atherosclerosis, where free oxCL is likely to be released from liberated mitochondria. Increased intracellular calcium could activate 5-LOX to produce Leukotriene B4 (LTB4). Annexin A5 inhibits the pro-inflammatory effects of oxCL and its potential therapeutic use when oxCL is implicated in inflammation could be of interest.
Authors: Ian A Myles; Kelli W Williams; Jensen D Reckhow; Momodou L Jammeh; Nathan B Pincus; Inka Sastalla; Danial Saleem; Kelly D Stone; Sandip K Datta Journal: JCI Insight Date: 2016-07-07
Authors: Justin R Buland; Karla J Wasserloos; Vladimir A Tyurin; Yulia Y Tyurina; Andrew A Amoscato; Rama K Mallampalli; Bill B Chen; Jing Zhao; Yutong Zhao; Solomon Ofori-Acquah; Valerian E Kagan; Bruce R Pitt Journal: Am J Physiol Lung Cell Mol Physiol Date: 2016-05-27 Impact factor: 5.464
Authors: Heather M Wilkins; Steven M Carl; Sam G Weber; Suruchi A Ramanujan; Barry W Festoff; Daniel A Linseman; Russell H Swerdlow Journal: J Alzheimers Dis Date: 2015 Impact factor: 4.472
Authors: Heather M Wilkins; Steven M Carl; Alison C S Greenlief; Barry W Festoff; Russell H Swerdlow Journal: Front Aging Neurosci Date: 2014-11-10 Impact factor: 5.750