Free fatty acids act as endogenous ionophores, resulting in Na+ and Ca2+ influx and myocyte apoptosis

Fang, Kwang-Ming; Lee, An‐Sheng; Su, Ming‐Jai; Lin, Chien-Liang; Chien, Chung‐Liang; Wu, Mei-Lin

doi:10.1093/cvr/cvn030

Cited by 35 publications

(26 citation statements)

References 38 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: 90%

“…The rapid lateral diffusion of the released saturated fatty acid in the plane of the inner membrane allows it to directly interact with the mPTP without sequestration by cytosolic fatty acid-binding proteins. The regulatory effects of palmitate on the mPTP are further aggravated by its ability to induce ER Ca 2ϩ depletion and reactive oxygen species generation (47,48) and by acting as an endogenous ionophore (49). Supporting these mechanisms, deletion of mitochondrial membrane-associated iPLA 2 ␥ led to the remarkable and robust salvage of damaged regions of myocardium after I/R, which emphasizes a prominent role of car- In addition to iPLA 2 ␥-mediated release of saturated fatty acids from phospholipid pools, we previously reported marked iPLA 2 ␥-dependent production of cardiac eicosanoids in the myocardium by utilizing cardiac myocyte-specific overexpression of iPLA 2 ␥ and global iPLA 2 ␥ knock-out mice (34).…”

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: 90%

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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“…They showed that different FFAs, including palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1), change. Fang et al ( 28 ) showed that arachidonic acid (20:0), palmitic acid (C16:0), oleic acid (C18:1), and linoleic acid (18:2) also play important roles during ischemic reperfusion, which impacts ion channels. Both palmitic and oleic acid induce intracellular Ca 2+ and Na + production in a dose-dependent manner by opening permeability transition pores.…”

Section: Discussionmentioning

confidence: 99%

Global changes in phospholipids identified by MALDI MS in rats with focal cerebral ischemia

Shanta

Choi

Lee

et al. 2012

Journal of Lipid Research

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has been given to cellular phospholipid analyses compared with protein or peptide analyses. However, recent progress in mass spectrometric analysis has enabled the identifi cation of small cellular components including phospholipids and quantifi cation of their cellular expression profi les ( 3, 4 ).ESI MS is widely used for phospholipid analysis. Currently, MALDI imaging MS (MALDI IMS) has become the prime choice because it provides additional advantages over ESI, including simple sample preparation and an abundance of information about molecular structures and spatial data ( 3,(5)(6)(7)(8)(9). The principal advantage of MALDI IMS is its ability to ionize molecules directly from the surface of tissue samples, which can demonstrate the spatial distribution of molecules of interest. However, MALDI IMS must be further improved to resolve technical problems such as the ambiguity of structural determination, unequal ionization effi ciencies of different compounds, and complications due to uneven tissue structure. Glycerophospholipids can be classifi ed according to their head groups, linkage between the polar chain and glycerol backbone, and variability in their FA composition ( 9 ). Depending on the presence of amine or hydroxyl structures on their head group, phospholipids can be ionized in either positive or negative mode. The ionization effi ciency of lipids can also be affected by their head group structure. Occasionally, it is diffi cult to perform MALDI IMS analysis twice in both positive and negative ionization modes on the same tissue sample to identify lipid composition Abstract Neuronal membrane phospholipids are highly affected by oxidative stress caused by ischemic injury. Thus, it is necessary to identify key lipid components that show changes during ischemia to develop an effective approach to prevent brain damage from ischemic injury. The recent development of MALDI imaging MS (MALDI IMS) makes it possible to identify phospholipids that change between damaged and normal regions directly from tissues. In this study, we conducted IMS on rat brains damaged by ischemic injury and detected various phospholipids that showed unique distributions between normal and damaged areas of the brain. Among them, we confi rmed changes in phospholipids such as lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin by MALDI IMS followed by MS/MS analysis. These lipids were present in high concentrations in the brain and are important for maintenance of cellular structure as well as production of second messengers for cellular signal transduction. Our results emphasize the identifi cation of phospholipid markers for ischemic injury and successfully identifi ed several distinctly located phospholipids in ischemic brain tissue.

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“…Accumulating evidence has indicated that AA is involved in cell apoptosis via the induction of Ca 2+ overload, increase in mitochondrial membrane permeability, release of cytochrome c and activation of caspase-3, which eventually leads to cell apoptosis and death [16,17] . Figure 3B and C).…”

Section: Gdcl 3 Inhibited A/r-induced Cardiomyocyte Apoptosis In Vitromentioning

confidence: 99%

“…Previous studies have demonstrated that mitochondrial-related pathways and death receptor-mediated pathways are involved in I/Rinduced cardiomyocyte apoptosis [13][14][15] . Therefore, the exploration of the mechanisms of myocardial I/R-induced apoptosis and the identification of the potential target(s) to prevent or reverse cell apoptosis are important for the prevention and Several studies have suggested that a large concentration of arachidonic acid (AA) is released from cell membrane phospholipids under pathological conditions, such as stress, ischemia, hypoxia, and I/R, thus leading to multiple deleterious consequences, including abnormal excitation-contraction coupling due to alterations in ion channel kinetics, bioenergetic inefficiency, apoptosis, and accelerated necrosis, which collectively promote the development of heart dysfunction, heart failure, and sudden death [16,17] . Accumulating evidence has indicated that AA-induced cell apoptosis partially occurs through mitochondria-mediated pathways via an increase in mitochondrial membrane permeability, the release of cytochrome c, and caspase-3 activation, which induces apoptosis and cell death [17] .…”

Section: Introductionmentioning

confidence: 99%

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

et al. 2016

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Aim:We have shown that low-dose gadolinium chloride (GdCl 3 ) abolishes arachidonic acid (AA)-induced increase of cytoplasmic Ca 2+ , which is known to play a crucial role in myocardial ischemia/reperfusion (I/R) injury. The present study sought to determine whether low-dose GdCl 3 pretreatment protected rat myocardium against I/R injury in vitro and in vivo. Methods: Cultured neonatal rat ventricular myocytes (NRVMs) were treated with GdCl 3 or nifedipine, followed by exposure to anoxia/ reoxygenation (A/R). Cell apoptosis was detected; the levels of related signaling molecules were assessed. SD rats were intravenously injected with GdCl 3 or nifedipine. Thirty min after the administration the rats were subjected to LAD coronary artery ligation followed by reperfusion. Infarction size, the release of serum myocardial injury markers and AA were measured; cell apoptosis and related molecules were assessed. Results: In A/R-treated NRVMs, pretreatment with GdCl 3 (2.5, 5, 10 μmol/L) dose-dependently inhibited caspase-3 activation, death receptor-related molecules DR5/Fas/FADD/caspase-8 expression, cytochrome c release, AA release and sustained cytoplasmic Ca 2+ increases induced by exogenous AA. In I/R-treated rats, pre-administration of GdCl 3 (10 mg/kg) significantly reduced the infarct size, and the serum levels of CK-MB, cardiac troponin-I, LDH and AA. Pre-administration of GdCl 3 also significantly decreased the number of apoptotic cells, caspase-3 activity, death receptor-related molecules (DR5/Fas/FADD) expression and cytochrome c release in heart tissues. The positive control drug nifedipine produced comparable cardioprotective effects in vitro and in vivo. Conclusion: Pretreatment with low-dose GdCl 3 significantly attenuates I/R-induced myocardial apoptosis in rats by suppressing activation of both death receptor and mitochondria-mediated pathways.

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Free fatty acids act as endogenous ionophores, resulting in Na+ and Ca2+ influx and myocyte apoptosis

Abstract: AA and FFAs, which accumulate in the myocardium during post-I/R, may therefore act as naturally occurring endogenous ionophores and contribute to the myocyte death seen during post-I/R.

Cited by 35 publications

References 38 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

Global changes in phospholipids identified by MALDI MS in rats with focal cerebral ischemia

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

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