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Pediatr Int. 2016 Dec;58(12):1266-1273. doi: 10.1111/ped.13022. Epub 2016 Jul 20.

Tolerance to ischemia reperfusion injury in a congenital heart disease model.

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Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.



Open heart surgery-associated ischemia/reperfusion (I/R) injury affects postoperative outcome, and a leading cause of this is lipid peroxidation. Congenital heart disease (CHD) patients, however, are less sensitive to I/R injury. Although little is known about the underlying molecular mechanisms, CHD-associated hypoxia alters the polyunsaturated fatty acid (PUFA) composition of membranes, which are the preferential targets for reactive oxygen species (ROS) generated during I/R. Here, using an animal model, we investigated the molecular mechanisms underlying I/R tolerance in CHD.


In order to reproduce I/R injury in vitro, we used a working heart perfusion model, isolated from juvenile control and CHD model rats (CHD rats), and examined the recovery of cardiac function during a period of I/R. PUFA composition of the plasma membrane was determined on gas chromatography/mass spectrometry. Oxidative stress-related cellular responses were investigated on immunoblotting, using antibodies against nuclear factor erythroid 2-related factor (Nrf-2), hemeoxygenase-1 (HO-1), and 4-hydroxy-2-hexanal (4-HHE)-modified protein.


Ischemia/reperfusion-induced cardiac dysfunction was markedly suppressed in CHD rats, compared with the control rats. n-3/n-6 PUFA ratio was significantly increased in both the pre- and post-I/R phase in CHD rats, but not in the controls. Four-HHE-modified protein, Nrf-2, and HO-1 were significantly increased in CHD rats as well, compared with the controls.


Following open heart surgery in CHD patients, the increased n-3/n-6 PUFA ratio may lead to the upregulation of cellular antioxidative system components through the oxidation product, 4-HHE, resulting in an increased tolerance to I/R injury.


antioxidant; congenital heart disease; ischemia/reperfusion injury; lipid peroxidation; polyunsaturated fatty acid

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