Mechanism of uncoupling protein 2­mediated myocardial injury in hypothermic preserved rat hearts.

In the present study, the alterations in uncoupling protein 2 (UCP2) expression following hypothermic preservation in rat hearts were investigated. Isolated rat hearts were preserved in Celsior solution for 3­12 h followed by 60 min of reperfusion. The cardiac function was evaluated using the Langendorff perfusion system. UCP2 and silent mating type information regulation 2 homolog 1 (SIRT1) proteins were detected by western blot analysis. The ATP production and mitochondrial reactive oxygen species (ROS) levels were assessed. Subsequent to preservation in ice­cold Celsior solution for 3­12 h, the UCP2 protein expression in rat hearts was observed to increase in a time­dependent manner. The UCP2 inhibitor genipin inhibited the hypothermic preservation­induced cardiac dysfunction, prevented a decline in ATP production induced by 9 h of preservation, however had no effect on the hypothermic preservation­induced increase in mitochondrial ROS levels. Compared with the control group, the SIRT1 protein expression in rat hearts reduced following hypothermic preservation. Compared with the 9­h preservation group, Celsior solution supplemented with the SIRT1 activator resveratrol (20 or 40 µmol/l) inhibited UCP2 protein overexpression, prevented the decline in ATP production and resulted in an improvement cardiac function. The SIRT1 inhibitor EX­527 abolished the resveratrol­induced inhibition of UCP2 overexpression and cardiac protection in the hypothermic preserved rat heart. These observations suggest that downregulation of UCP2 expression in the hypothermic preserved rat heart in part initiated the protective mechanism via the SIRT1 pathway.

Mitochondrial aldehyde dehydrogenase activity protects against lipopolysaccharide­induced cardiac dysfunction in rats.

Myocardial dysfunction in sepsis is associated with an increased risk of mortality. The mitochondrial aldehyde dehydrogenase (ALDH2) enzyme is crucial for protecting the heart from ischemic injury. The aim of the present study was to determine the role of ALDH2 in cardiac dysfunction induced by lipopolysaccharide (LPS). Male rats were treated intraperitoneally with LPS, and their stroke volume and cardiac output were evaluated using an M­mode echocardiograph. The expression levels and activity of ALDH2, nitric oxide content and inducible nitric oxide synthase (iNOS) activity, and the opening of the mitochondrial permeability transition pore (MPTP) were also evaluated. Treatment with LPS (5, 10, or 20 mg/kg) resulted in a steady decrease in cardiac output and stroke volume. The ALDH2 activity was decreased in a dose­dependent manner; however, the ALDH2 protein expression levels remained unchanged. Alda­1, a specific activator of ALDH2, increased the activity of ALDH2 and lessened LPS­induced cardiac dysfunction. A marked opening of the MPTP was observed 12 h following treatment with LPS, which was prevented by Alda­1. The improvement in cardiac function in response to treatment with Alda­1, was partially prevented by treatment with the MPTP inhibitor atractyloside. LPS treatment induced an increase in iNOS activation and inhibition of ALDH2 activity. The iNOS selective inhibitor, aminoguanidine, partially reversed the LPS­induced ALDH2 activity decrease and MPTP opening. These results indicate that ALDH2 activity may have a role in protecting against LPS­induced cardiac dysfunction. The potential mechanism may involve inhibition of MPTP opening and iNOS expression.