Heart failure–induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore

Moon, Sung Ho; Liu, Xinping; Cedars, Ari; Yang, Kui; Kiebish, Michael A.; Joseph, Susan; Kelley, John; Jenkins, Christopher M.; Gross, Richard W.

doi:10.1074/jbc.ra117.000405

Cited by 42 publications

(38 citation statements)

References 50 publications

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“…ARA oxylipins are associated with several functional effects in the heart. For example, increased PGF 2α and PGE 2 are associated with hypertrophic growth and production of arrhythmias in neonatal cardiac myocytes (40,46,47) , the lipoxygenase-generated HETE are increased in mitochondria from failing human hearts (48) and 20-HETE induces vasoconstriction in small porcine coronary arteries (49) . Some effects of ARA oxylipins are protective, however, such as the vasodilatory EpETrE, which may prevent obesity-induced cardiomyopathy and reduce postischaemic ventricular polarisation in an isolated heart model (50,51) , and PGI 2 , which displays protective effects against the arrhythmias induced by other prostanoids in rat cardiac myocytes (40) .…”

Section: Discussionmentioning

confidence: 99%

Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts

et al. 2019

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Oxylipins are bioactive lipid mediators synthesised from PUFA. The most well-known oxylipins are the eicosanoids derived from arachidonic acid (ARA), and many of them influence cardiac physiology in health and disease. Oxylipins are also formed from other n-3 and n-6 PUFA such as α-linolenic acid (ALA), EPA, DHA and linoleic acid (LA), but fundamental data on the heart oxylipin profile, and the effect of diet and sex on this profile, are lacking. Therefore, weanling female and male Sprague–Dawley rats were given American Institute of Nutrition (AIN)-93G-based diets modified in oil composition to provide higher levels of ALA, EPA, DHA, LA and LA + ALA, compared with control diets. After 6 weeks, free oxylipins in rat hearts were increased primarily by their precursor PUFA, except for EPA oxylipins, which were increased not only by dietary EPA but also by dietary ALA or DHA. Dietary DHA had a greater effect than ALA or EPA on reducing ARA oxylipins. An exception to the dietary n-3 PUFA-lowering effects on ARA oxylipins was observed for several ARA-derived PG metabolites that were higher in rats given EPA diets. Higher dietary LA increased LA oxylipins, but it had no effect on ARA oxylipins. Overall, heart oxylipins were higher in female rats, but this depended on dietary treatment: the female oxylipin:male oxylipin ratio was higher in rats provided the ALA compared with the DHA diet, with other diet groups having ratios in between. In conclusion, individual PUFA and sex have unique and interactive effects on the rat heart free oxylipin profile.

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Section: Discussionmentioning

confidence: 99%

Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts

et al. 2019

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“…The link between polyunsaturated fats such as arachidonic acid and mPTP opening could involve the mediation of hydroxyeicosatetraenoic acids (HETEs) generated via lipoxygenase action. HETEs are known to activate Ca 2+ -induced opening of the mPTP in, for example, the failing heart, and exposure to lipoxygenase inhibitors has been found to attenuate this process (Moon et al 2018). Under normal circumstances, the unsaturated fat that dominates the sperm lipid profile, decosahexaenoic acid, might be expected to suppress mPTP opening (Khairallah et al 2010).…”

Section: Polyunsaturated Fats and Lipoxygenasementioning

confidence: 99%

Impact of oxidative stress on male and female germ cells: implications for fertility

2020

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Male and female germ lines are vulnerable to oxidative stress. In spermatozoa, such stress triggers a lipid peroxidation cascade that culminates in the generation of electrophilic lipid aldehydes that bind to DNA and a raft of proteins involved in the delivery of functionally competent cells. One set of targets for these aldehydes are the proteins of the mitochondrial electron transport chain. When this interaction occurs, mitochondrial ROS generation is enhanced leading to the sustained generation of oxidative damage in a self-perpetuating cycle. Such damage affects all aspects of sperm function including motility, sperm-egg recognition, acrosomal exocytosis and sperm-oocyte fusion. Oxidative stress in the male germ line also attacks the integrity of sperm DNA with potential impacts on the developmental capacity of embryos and the health and wellbeing of the offspring. Potential pathways of reactive oxygen species (ROS) generation in male germ cells could involve enhanced lipoxygenase activity, activation of NADPH oxidase and/or electron leakage from mitochondria. Similarly, in the female germ line, both the induction of oocyte senescence following ovulation and the deterioration of oocyte quality with maternal age appear to involve the generation of oxidative damage. In this case, the mitochondria appear to be a particularly important source of ROS compromising the viability and fertilizability of the oocyte and interfering with the normal segregation of chromosomes during meiosis. In light of these considerations, antioxidants should have some role to play in the preservation of reproductive function in both men and women; however, we still await appropriate trials to test this hypothesis.

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“…Tissue from the left ventricle and left ventricular apex of nonfailing human hearts was obtained from organ donors having a heart deemed unsuitable for transplantation due to donor age, epicardial (nonocclusive) coronary vascular disease, or high risk behavioral profile. All tissue was trimmed of excess fat, washed in cold PBS, and then placed in ice-cold MIB prior to isolation of mitochondria by differential centrifugation as described previously (84).…”

Section: Collection Of Human Heart Tissue and Isolation Of Mitochondriamentioning

confidence: 99%

Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage

Jenkins

Yang

Liu

et al. 2018

Journal of Biological Chemistry

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Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl ether linkage at the -1 position and are highly enriched in arachidonic acid (AA) at the-2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive. Herein, we report that cytochrome , in the presence of either cardiolipin (CL), O and HO, or oxidized CL and O, catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive α-hydroxy fatty aldehydes. Using stable isotope labeling in synergy with strategic chemical derivatizations and high-mass-accuracy MS, we deduced the chemical mechanism underlying this long sought-after reaction. Specifically, labeling with either O or HO, but not with HO, resulted in M + 2 isotopologues of the α-hydroxyaldehyde, whereas reactions with both O and HO identified the M + 4 isotopologue. Furthermore, incorporation of O fromO was predominantly located at the α-carbon. In contrast, reactions with HO yielded O linked to the aldehyde carbon. Importantly, no significant labeling of 2-AA-lysolipids withO, HO, or HO was present. Intriguingly, phosphatidylinositol phosphates (PIP and PIP) effectively substituted for cardiolipin. Moreover, cytochrome released from myocardial mitochondria subjected to oxidative stress cleaved plasmenylcholine in membrane bilayers, and this was blocked with a specific mAb against cytochrome Collectively, these results identify the first plasmalogenase in biology, reveal the production of previously unanticipated signaling lipids by cytochrome, and present new perspectives on cellular signaling during oxidative stress.

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Heart failure–induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore

Cited by 42 publications

References 50 publications

Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts

Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts

Impact of oxidative stress on male and female germ cells: implications for fertility

Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage

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