In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 302, No. 10 ( 2012-05-15), p. H2018-H2030
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.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00955.2011
Language:
English
Publisher:
American Physiological Society
Publication Date:
2012
detail.hit.zdb_id:
1477308-9
SSG:
12
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