title: Disruption of group IVA cytosolic phospholipase A(2) attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway.
abstract: Group IVA cytosolic phospholipase A(2) (cPLA(2)α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)α activation. This study examined the potential role of cPLA(2)α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA(2)α knockout (cPLA(2)α(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)α(+/+)) mice, cPLA(2)α(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) mice. sTNFR:Fc also suppressed cPLA(2)α phosphorylation in the ischemic myocardium after I/R of cPLA(2)α(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) cardiomyocytes. H/R and TNF-α induced cPLA(2)α phosphorylation in cPLA(2)α(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)α(-/-) cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)α(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.
authors.affiliation: Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Saito
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujioka
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Jun-ei
authors.initials: JE
authors.lastname: Obata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kawabata
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hideto
authors.initials: H
authors.lastname: Mishina
authors.forename: Shun
authors.initials: S
authors.lastname: Tamaru
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kita
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kugiyama
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000068800:Etanercept; D054513:Group IV Phospholipases A2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000502:physiology*; D013929:Thromboxane B2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D013929:Thromboxane B2; D054513:Group IV Phospholipases A2; D000068800:Etanercept