Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation - A novel mechanism for the cardioprotective effects of PPAR agonists

Abstract

Aims: Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have recently been shown to reduce ischaemic heart injury in hypercholesterolaemic animals. However, whether PPARγ 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 PPARγ agonists may have great therapeutic value in ischaemic heart disease patients with multiple complications such as hypercholesterolaemia and diabetes. © The Author 2008.