Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn308
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Rosiglitazone Inhibits Hypercholesterolemia-Induced Myeloperoxidase Upregulation -a Novel Mechanism for the Cardioprotective Effects of PPAR Agonists
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107
* Address proofs to: Xin L Ma, M.D., Ph.D., Department of Emergency Medicine, 1020 Sansom Street, Thompson Building, Room 241, Philadelphia, PA 19107, Tel: (215)955-4994, Fax: (215)923-6225, E-mail: Xin.Ma{at}Jefferson.edu
Aims: Hypercholesterolemia and myeloperoxidase overexpression are two well-recognized risk factors for ischemic heart disease. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have recently been shown to reduce ischemic heart injury in hypercholesterolemic animals. However, whether PPARγ agonists may exert their cardioprotective effects by eliminating those risk factors that increase ischemic injury remains unknown.
Materials and Methods: Male New Zealand rabbits were fed with a normal or 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 ischemia/reperfusion (1 hour/4 hours). Myeloperoxidase expression, activity, and distribution, cardiac caspase 3 activity and myocardial infarct size were determined. Diet-induced hypercholesterolemia caused a significant increase in neutrophil myeloperoxidase expression/activity (7.2-fold/5.4-fold). Hypercholesterolemia also tripled myeloperoxidase activity in ischemic/reperfused hearts when compared with rabbits fed with a normal diet. Surprisingly, myeloperoxidase immunostaining was not only observed in perivascular and extracellular spaces in ischemic/reperfused hearts, but also in cardiomyocytes. This intracardiomyocyte myeloperoxidase staining was further intensified by hypercholesterolemia. There is a strong positive correlation between cardiac myeloperoxidase activity and caspase 3 activity, and treatment with a myeloperoxidase inhibitor significantly reduced post-ischemic caspase 3 activation. Treatment with RSG markedly inhibited hypercholesterolemia-induced leukocyte myeloperoxidase overexpression and activation, reduced myeloperoxidase activity in ischemic/reperfused hearts, decreased caspase 3 activity and reduced myocardial infarct size (P<0.01).
Conclusions: Our results demonstrated that hypercholesterolemia and myeloperoxidase overexpression are causally related and that PPARγ agonists may have great therapeutic value in ischemic heart disease patients with multiple complications such as hypercholesterolemia and diabetes.
KEYWORDS Cholesterol homeostasis; Myocardial inflammation; Myocyte apoptosis and necrosis; Reperfusion Injury
Time for primary review: 30 Days
1 These two authors contributed to this work equally. Permanent address for HR Liu: Cardiovascular Research Institute, Capital Medical University, Beijing, P.R. China
2 Center for Translational Medicine, Thomas Jefferson University
3 GlaxoSmithKline Pharmaceuticals, King of Prussia, PA
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