12(S)-Hydroperoxyeicosatetraenoic acid (12-HETE) increases mitochondrial nitric oxide by increasing intramitochondrial calcium

Nazarewicz, Ryszard; Zenebe, Woineshet J.; Parihar, Arti; Parihar, Mordhwaj S.; Vaccaro, Michael; Rink, Cameron; Sen, Chandan K.; Ghafourifar, Pedram

doi:10.1016/j.abb.2007.09.018

Cited by 55 publications

(43 citation statements)

References 36 publications

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“…12-HETE, 20-HETE, and 8-HDoHE), but not 14,15-EET, 9-oxoODE, or PGE 2 , sensitize mitochondria to the calcium-induced loss of membrane potential. These findings are supported by previous studies that showed arachidonic acid-and 12-HETE-facilitated Ca 2ϩ overload resulting in abnormal oxidative stress and mitochondrial dysfunction (44,49). Therefore, the results of this study suggest that iPLA 2 ␥ facilitates production of oxidized lipid metabolites by providing PUFAs and/or polyunsaturated fatty acyl lysolipids, which can be further hydrolyzed to non-esterified PUFAs by lysophospholipases and subsequent oxidation by downstream oxygenases.…”

Section: Discussionsupporting

confidence: 79%

“…mitophagy). This study demonstrates the unanticipated and dramatic accumulation of oxidized fatty acids, including large amounts of oxidized linoleic acid metabolites, which likely originate from cardiolipin, the major pool of esterified linoleic acid in the mitochondrial compartment as well as a plethora of eicosanoid metabolites known to have adverse effects on cardiac myocyte membrane proteins, inflammation, and bioenergetics (43)(44)(45). The benefits of iPLA 2 ␥ loss of function investigated in this study include the attenuation of many of the molecular mechanisms known to predispose to myocardial tissue damage during pathological processes, including cardiac ischemia/reperfusion (46).…”

Section: Discussionmentioning

confidence: 99%

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Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2γ (iPLA2γ) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size

Moon

Mancuso

Sims

et al. 2016

Journal of Biological Chemistry

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Calcium-independent phospholipase A 2 ␥ (iPLA 2 ␥) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA 2 ␥ in cardiac myocytes, we generated cardiac myocyte-specific iPLA 2 ␥ knock-out (CMiPLA 2 ␥KO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA 2 ␥KO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA 2 ␥KO mice demonstrated attenuated Ca 2؉ -induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA 2 ␥KO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA 2 ␥KO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-atrisk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca 2؉ by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA 2 ␥, these results are consistent with salvage of myocardium after I/R by iPLA 2 ␥ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion.The salvage of jeopardized regions of myocardium during ischemia/reperfusion (I/R) 3 has been a long-standing goal of heart research. Because mortality and morbidity are related to infarct size, a variety of hemodynamic, metabolic, and pharmacological approaches have been used to reduce the severity of myocardial infarction during ischemia (1-3). Recent studies have accumulated evidence that the irreversible opening of the mitochondrial permeability transition pore (mPTP) upon oxidative stress is a principal mechanism of apoptotic/necrotic cardiac cell death accounting for the majority of I/R injury (4 -6). Although therapies for acute ischemia (e.g. reperfusion) have been extensively studied, at present there is no therapy for attenuating mPTP opening during reperfusion of ischemic zones in myocardium.Although the precise chemical composition of the mPTP is incompletely understood (6), a variety of initiators and modulators of mPTP opening has been identified (7,8). For example, during reperfusion, the reoxygenation of ischemic tissue results in mitochondrial Ca 2ϩ overload and renormalization of intracellular and matrix pH, which are accompanied by the prodigious generation of reactive oxygen s...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2γ (iPLA2γ) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size

Moon

Mancuso

Sims

et al. 2016

Journal of Biological Chemistry

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“…For example, lipoxygenase inhibi- tion has been demonstrated to block insulin-mediated glucose uptake in cultured ventricular myocytes suggesting the importance of downstream lipoxygenase metabolites in insulin signaling (61). Furthermore, 12-HETE has been previously demonstrated to increase myocardial mitochondrial Ca 2ϩ content as well as mitochondrial nitric-oxide synthase activity, which led to increased apoptosis in HL-1 cardiac myocytes (51,62). Intriguingly, arachidonic acid has been implicated in MPT pore opening in several tissues, and inhibition of the release of AA from mitochondria prevented pore opening (42,63).…”

Section: Discussionmentioning

confidence: 99%

Activation of Mitochondrial Calcium-independent Phospholipase A2γ (iPLA2γ) by Divalent Cations Mediating Arachidonate Release and Production of Downstream Eicosanoids

Moon

Jenkins

Liu

et al. 2012

Journal of Biological Chemistry

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Background: Calcium-independent PLA 2 ␥ is a major phospholipase in cardiac mitochondria that modulates multiple mitochondrial functions, but its mechanism of activation is unknown. Results: Divalent cations activate iPLA 2 ␥ leading to release of eicosanoids and lysolipids from mitochondrial phospholipids. Conclusion: Divalent cation-activated mitochondrial iPLA 2 ␥ initiates the production of biologically active signaling metabolites. Significance: iPLA 2 ␥ contributes to regulation of myocardial bioenergetic and electrophysiologic functions by production of eicosanoids.

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“…Further mechanisms of 12-HETE action include stimulating oxidative stress by increasing intramitochondrial ionized calcium concentrations in cardiac myocyte mitochondria and stimulating mitochondrial nitric oxide synthase activity, which goes on to induce cell apoptosis (16). A study of beta cells in the pancreases of diabetic patients showed that inflammatory cytokines can induce 12-lipoxygenase RNA and protein expression and that an increase in 12-HETE levels inhibits insulin secretion, reduces beta cell metabolic activity, and induces cell death in islet cells (17,18).…”

Section: Discussionmentioning

confidence: 99%

ALOX12 in Human Toxoplasmosis

et al. 2014

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jALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen to arachidonic acid, producing 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which can be reduced to the eicosanoid 12-HETE (12-hydroxyeicosatetraenoic acid). 12-HETE acts in diverse cellular processes, including catecholamine synthesis, vasoconstriction, neuronal function, and inflammation. Consistent with effects on these fundamental mechanisms, allelic variants of ALOX12 are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined. Toxoplasma gondii is an apicomplexan parasite that causes morbidity and mortality and stimulates an innate and adaptive immune inflammatory reaction. Recently, it has been shown that a gene region known as Toxo1 is critical for susceptibility or resistance to T. gondii infection in rats. An orthologous gene region with ALOX12 centromeric is also present in humans. Here we report that the human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis (rs6502997 [P, <0.000309], rs312462 [P, <0.028499], rs6502998 [P, <0.029794], and rs434473 [P, <0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knock down ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and levels of the ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated the progression of T. gondii infection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest that ALOX12 influences host responses to T. gondii infection in human cells. ALOX12 has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12 plays in T. gondii infection in humans.

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12(S)-Hydroperoxyeicosatetraenoic acid (12-HETE) increases mitochondrial nitric oxide by increasing intramitochondrial calcium

Cited by 55 publications

References 36 publications

Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2γ (iPLA2γ) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size

Cardiac Myocyte-specific Knock-out of Calcium-independent Phospholipase A2γ (iPLA2γ) Decreases Oxidized Fatty Acids during Ischemia/Reperfusion and Reduces Infarct Size

Activation of Mitochondrial Calcium-independent Phospholipase A2γ (iPLA2γ) by Divalent Cations Mediating Arachidonate Release and Production of Downstream Eicosanoids

ALOX12 in Human Toxoplasmosis

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