期刊
CARDIOVASCULAR RESEARCH
卷 81, 期 2, 页码 344-352出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn308
关键词
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资金
- American Diabetes Association [7-08-RA-98, 7-06-JF59]
- American Heart Association [GIA0855554D]
- Commonwealth of Pennsylvania Department of Health
- [NIH 2R01HL-63828,]
Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists have recently been shown to reduce ischaemic heart injury in hypercholesterolaemic animals. However, whether PPAR gamma agonists may exert their cardioprotective effects by eliminating those risk factors that increase ischaemic injury remains unknown. 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). Our results demonstrated that hypercholesterolaemia and MPO overexpression are causally related and that PPAR gamma agonists may have great therapeutic value in ischaemic heart disease patients with multiple complications such as hypercholesterolaemia and diabetes.
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