More than one million new and recurrent cases of coronary attack occurred in the US in 1998. Forty percent of these patients died, 220,000 before even reaching hospital, making coronary heart disease the single leading cause of death in America. Heart disease most commonly results from atherosclerosis and associated risk factors including obesity and hyperlipidemia. Treatment is thus designed to slow the development of atherosclerosis, usually through the use of anti-thrombotic and/or anti-coagulant therapies, or in the event of coronary attack to reverse ischemia, limit infarct size, reduce cardiac work and to prevent recurrence. Immediate treatment of myocardial infarction includes the use of thrombolytics to reverse ischemia (see "Heart/Cardiovascular disease 2002" for an analysis of pharmaceutical opportunities in this area). Peroxisomal proliferator-activated receptor (PPAR) is a ligand-activated transcription factor that regulates gene expression in response to various mediators and has been extensively studied in relation to diabetes with the result that a number of PPAR activators are now marketed for this condition. In addition to reducing the development of insulin resistance, PPAR ligands are able to limit atherosclerosis and may therefore be of use in the prevention of myocardial infarction. Most recently a number of studies have been published reporting the ability of PPAR ligands to limit the effects of myocardial infarction. For example the PPAR-alpha agonist, fenofibrate, reduces myocardial infarction size and improves post-ischaemic contractile dysfunction in a mouse model. On the other hand, hearts from PPARalpha null mice exhibit increased susceptibility to ischemic damage and were refractory to protection by fenofibrate treatment. Furthermore, fenofibrate improves endothelium- and nitric oxide-mediated vasodilatation in aorta and mesenteric vascular bed. Researchers from the William Harvey Research Institute have since extended these findings showing that various distinct PPAR-alpha and –gamma ligands were protective in a rat model of myocardial infarction. This group suggests that the effects of PPAR-gamma ligands may be due to 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. Whatever the mechanism this data is particularly exciting since it suggests that protection against and treatment of myocardial infarction should be added to the growing list of indications for PPAR ligands.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk