Abstract
Myocardial ischemia/reperfusion (I/R) injury in hypercholesterolemia is associated with oxidative stress, while luteolin is known to reduce oxidative stress by activating Akt/nuclear factor erythroid-2-related factor 2 (Nrf2) signaling and alleviate cardiac I/R injury. Here, we investigated whether luteolin pretreatment diminishes myocardial I/R injury in hypercholesterolemic rats by activating Akt/Nrf2 signaling. Hypercholesterolemic rats were produced by 2% cholesterol diet for 8 weeks. Luteolin (100 mg/kg/day, i.g.) or LY294002 was administered for the last 2 weeks. The hearts were then isolated and subjected to 30 min of global ischemia followed by 120 min of reperfusion. Pretreatment with luteolin significantly improved left ventricular function throughout reperfusion, increased cardiac tissue viability, reduced coronary lactate dehydrogenase release and the myocardial malondialdehyde level, upregulated p-Akt and p-GSK3β expressions, inhibited nuclear translocation of Fyn, and activated Nrf2 function in hypercholesterolemic I/R rat hearts. All these improving effects of luteolin were significantly attenuated by LY294002. Ca2+-induced mitochondrial permeability transition pore (mPTP) opening and mitochondrial inner membrane potential reduction were significantly inhibited in ventricular myocytes isolated from luteolin-treated hypercholesterolemic rats, which were attenuated by LY294002. These results indicate that luteolin protects the hypercholesterolemic heart against I/R injury due to upregulation of Akt-mediated Nrf2 antioxidative function and inhibition of mPTP.
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Funding
This work was supported by Foundation from Science and Technology Department of Zhejiang Province (2016C37133), Chinese Medicine Research Program of Zhejiang Province (2016ZA045), National Natural Science Foundation of China (81772035, 81600203 and 81671883), and the Program of Cultivating Zhejiang Provincial High-level Personnel in Health (Excellent Medical Younger in 2018).
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All the protocols conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (the 8th Edition, NRC 2011) and were approved by the Experimental Animals Ethics Committee in Hangzhou Medical College.
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Yang, JT., Wang, J., Zhou, XR. et al. Luteolin alleviates cardiac ischemia/reperfusion injury in the hypercholesterolemic rat via activating Akt/Nrf2 signaling. Naunyn-Schmiedeberg's Arch Pharmacol 391, 719–728 (2018). https://doi.org/10.1007/s00210-018-1496-2
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DOI: https://doi.org/10.1007/s00210-018-1496-2