Cardiovascular Research Advance Access first published online on November 14, 2008
This version [Corrected Proof] published online on December 4, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn308
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Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation—a novel mechanism for the cardioprotective effects of PPAR agonists
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1 Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Thompson Building, Room 241, Philadelphia, PA 19107, USA
2 Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA
3 GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA
* Corresponding author. Tel: +1 215 955 4994; fax: +1 215 923 6225.E-mail address: xin.ma{at}jefferson.edu
Aims: Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-
(PPAR) agonists have recently been shown to reduce ischaemic heart injury in hypercholesterolaemic animals. However, whether PPAR agonists may exert their cardioprotective effects by eliminating those risk factors that increase ischaemic injury remains unknown.
Methods and results: Male New Zealand rabbits were fed with a normal or a high-cholesterol diet for 8 weeks, treated with vehicle or rosiglitazone (RSG, 3 mg/kg/day for the last 5 weeks) and subjected to myocardial ischaemia/reperfusion (1 h/4 h). MPO expression, activity, and distribution, cardiac caspase-3 activity, and myocardial infarct size were determined. Diet-induced hypercholesterolaemia caused a significant increase in neutrophil MPO expression/activity (7.2-/5.4-fold). Hypercholesterolaemia also tripled MPO activity in ischaemic/reperfused hearts when compared with rabbits fed with a normal diet. Surprisingly, MPO immunostaining was not only observed in perivascular and extracellular spaces in ischaemic/reperfused hearts, but also in cardiomyocytes. This intracardiomyocyte MPO staining was further intensified by hypercholesterolaemia. There is a strong positive correlation between cardiac MPO activity and caspase-3 activity, and treatment with an MPO inhibitor significantly reduced post-ischaemic caspase-3 activation. Treatment with RSG markedly inhibited hypercholesterolaemia-induced leucocyte MPO overexpression and activation, reduced MPO activity in ischaemic/reperfused hearts, decreased caspase-3 activity, and reduced myocardial infarct size (P < 0.01).
Conclusion: Our results demonstrated that hypercholesterolaemia and MPO overexpression are causally related and that PPAR agonists may have great therapeutic value in ischaemic heart disease patients with multiple complications such as hypercholesterolaemia and diabetes.
KEYWORDS Cholesterol homeostasis; Myocardial inflammation; Myocyte apoptosis and necrosis; Reperfusion injury
Time for primary review: 30 days
Present address. Cardiovascular Research Institute, Capital Medical University, Beijing, People's Republic of China.
These authors contributed equally to this work.
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