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Abstract Number: 569

Hydroxycholorquine Is Cardioprotective In Neonatal Rat Cardiomyocytes Exposed To Simulated Myocardial Ischaemic/Reperfusion Injury.-An Effect Mediated Through ERK Phosphorylation

Lauren Bourke1, James McCormick2, Anastasis Stephanou3 and Yiannis Ioannou4, 1Centre for Rheumatology Research, University College London, London, United Kingdom, 2Clinical & Molecular Genetics Unit, University College London, London, United Kingdom, 3MMBU, University College London, London, United Kingdom, 4Arthritis Research UK Centre for Adolescent Rheumatology at University College London, Great Ormond Street Hospital and UCLH, University College London, London, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Apoptosis, Cardiovascular disease, hydroxychloroquine and systemic lupus erythematosus (SLE)

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Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose:

A significant amount of myocardial damage during a myocardial infarction (MI) occurs during the reperfusion stage which is known as ischaemic reperfusion (I/R) injury and can account for up to 50% of cell death. Systemic Lupus Erythematosus (SLE) is a condition associated with a high burden of cardiovascular morbidity and mortality, when compared to the matched healthy population. A large proportion of these patients are treated with the anti-malarial drug Hydroxycholoroquine (HCQ) and whilst retrospective studies have suggested that SLE patients prescribed HCQ have a reduced risk of suffering an MI, inevitably there are patients who still do. Therefore the purpose of this study is to determine whether HCQ has an effect on the injury occurring during the reperfusion stage.

Methods:

We utilised an established in vitro model of anoxia/reoxygenation to simulate ischaemic reperfusion (I/R) injury. Cardiomyocytes were isolated from 1-2 day old rat pups and when beating synchronously were treated with 1-2 µg/ml HCQ and the following day exposed to simulated I/R injury for 4hr in a hypoxic chamber (argon, 5% CO2) followed by a time-course of reoxygenation. Total cell death was measured using a colorimetric cell proliferation assay (CellTiter96 Aqueous Cell Proliferation Assay) and apoptosis assessed using a TUNEL kit and assessment of caspase-3 cleavage by immunoblot. The activation of ERK, p-38, JNK and Akt were also assessed by immunoblot.

Results:

Treatment of neonatal rat cardiomyocytes with HCQ prior to simulated I/R injury was protective and reduced cell death, specifically apoptosis.  This was observed using TUNEL which showed that cells exposed to hypoxia alone saw a 20.7% (±SD 7.4) increase in TUNEL positivity when compared with cells in optimal conditions. This was further increased to 30.1 % (±SD 7.0)(p value < 0.001) after reoxygenation and in the presence of HCQ  was abrogated back down to16.93 % (±SD 3.0)(p value <0.0001). This was confirmed by an increase in cleaved caspase-3 (0.24 relative to GAPDH (±SD 0.10) (p value < 0.0001)) in cells exposed to simulated I/R injury when compared to cells in optimal conditions (0.03 relative to GAPDH (±SD 0.03)). In the presence of HCQ this increase in caspase-3 cleavage was reduced by 54% (0.11 relative to GAPDH (± SD 0.06) (p value < 0.01)).  The colorimetric cell proliferation assay confirmed that HCQ caused a reduction in total cell death in cells exposed to simulated I/R injury of 57.89%. Correlating with decreased cell death, enhanced ERK phosphorylation in HCQ treated cells was observed in a dose-dependent manner and no significant differences in p38, JNK and Akt were observed. Cells treated with HCQ and exposed to simulated I/R injury were incubated with the ERK inhibitor U1026 and protective effects of HCQ as assessed via caspase-3 cleavage was completely reversed.

Conclusion:

HCQ is cardioprotective in this in vitro I/R injury model and results suggest this protection is dependent upon up-regulation of ERK phosphorylation. Experiments are now being performed to confirm this observation using an in vivo I/R injury animal model.


Disclosure:

L. Bourke,
None;

J. McCormick,
None;

A. Stephanou,
None;

Y. Ioannou,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hydroxycholorquine-is-cardioprotective-in-neonatal-rat-cardiomyocytes-exposed-to-simulated-myocardial-ischaemicreperfusion-injury-an-effect-mediated-through-erk-phosphorylation/

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