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Luteolin ameliorates rat myocardial ischaemia-reperfusion injury through activation of peroxiredoxin II.

ABSTRACT: BACKGROUND AND PURPOSE:Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin, a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanisms, especially the role of luteolin on the antioxidant enzymes, such as the peroxiredoxin family, remain unknown. EXPERIMENTAL APPROACH:We measured the effects of luteolin on myocardial ischaemia/reperfusion (MI/R) injury in vivo (Sprague-Dawley rats) and in vitro, together with the underlying mechanisms, with a focus on signalling by peroxiredoxins. H9c2 cells were used to assess the changes in peroxiredoxins and the other antioxidant enzymes. Oxidative stress, cardiac function, LDH release, ROS and infarct size were also assayed. KEY RESULTS:Luteolin exerted significant cardioprotective effects in vivo and in vitro via improving cardiac function, increasing the expression of anti-apoptotic protein Bcl-2 and decreasing the pro-apoptotic protein Bax and active caspases 3 and 9, associated with MI/R. Mechanistically, luteolin markedly enhanced expression of peroxiredoxin II, without significant effects on other forms of peroxiredoxin, catalase or SOD1. Molecular docking showed that luteolin could indeed bind to the enzymic active pocket of peroxiredoxin II. Furthermore, down-regulation of peroxiredoxin II by peroxiredoxin II-antisense, administered by adenovirus infection of H9c2 cardiomyocytes, and inhibition of peroxiredoxin II in vivo significantly reversed the cardioprotective effects of luteolin. CONCLUSIONS AND IMPLICATIONS:Our findings, for the first time, demonstrate that luteolin protects against MI/R injury through promoting signalling through the endogenous antioxidant enzyme, peroxiredoxin II, indicating the important beneficial role of this antioxidant system in the heart.

SUBMITTER: Wei B

PROVIDER: S-EPMC6057904 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Luteolin ameliorates rat myocardial ischaemia-reperfusion injury through activation of peroxiredoxin II.

Wei Bo B Lin Qiao Q Ji Ya-Ge YG Zhao Yi-Can YC Ding Li-Na LN Zhou Wen-Juan WJ Zhang Li-Hua LH Gao Chuan-Yu CY Zhao Wen W

British journal of pharmacology 20180704 16

<h4>Background and purpose</h4>Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin, a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanisms, especially the role of luteolin on the antioxidant enzymes, such as the peroxiredoxin family, remain unknown.<h4>Experimental approach</h4>We measured the effects of luteolin on myocardial ischaemia/reperfusion (MI/R) injury in vivo (Sprague-Dawley rats) and in vitro, toge ...[more]

PMID: 29782637

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Project description:Aims:Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results:OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24?h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P?<?0.05 to P?<?0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6?±?4.14% and with PONPC was 25.3?±?3.4% compared to 8.0?±?1.6% and 6.4?±?1.0%, respectively, with the addition of E06, P?<?0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4?±?21.9% vs. 47.7?±?17.6%, P?=?0.023). Conclusions:OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.

Dataset Information

Luteolin ameliorates rat myocardial ischaemia-reperfusion injury through activation of peroxiredoxin II.

Publications

Luteolin ameliorates rat myocardial ischaemia-reperfusion injury through activation of peroxiredoxin II.

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