Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options.
Biomarkers such as C-reactive protein (CRP) and myeloperoxidase (MPO) are elevated in patients with coronary artery disease and confer risk of acute cardiovascular events, such as myocardial infarction (MI) and stroke. More recently, variants in the 5-lipoxygenase-activating protein (FLAP) gene were shown to confer risk to both MI and stroke, effects that appear to be mediated through elevated LTB(4), a chemoattractant mediator shown to be upregulated in patients with MI. Another gene in the leukotriene (LT) pathway, LTA(4) hydrolase, was subsequently found to confer increased risk to MI, effects that were ethnicity-specific with an approximately threefold higher risk in African Americans than in whites. In another study, markers in the phosphodiesterase (PDE) 4D gene were found to confer risk to large-vessel occlusive and cardiogenic stroke. Interestingly, there is a cross-link between the 5-LO and the PDE4D pathways with converging biology. To address the role of an inhibitor of FLAP on biomarkers of MI risk, a randomized placebo-controlled phase II trial was conducted in patients with MI. This trial showed that LTB(4) and MPO production was reduced in whole blood leukocytes that were stimulated with ionomycin and the effects of the inhibitor were dose dependent. Serum CRP and plasma MPO were also reduced at the highest dose, which was well tolerated. These data suggest that LTB(4) is a risk factor of MI and that inhibition of FLAP and the LT pathway produces suppression of biomarkers that are associated with MI risk, including but not limited to LTB(4), MPO, and CRP, supporting the notion that the LTB(4) arm of the LT pathway may play a fundamental role in heart attacks and stroke.
Hakonarson
Hakon
H
deCODE Genetics Inc., Sturlugata 8, 101 Reykjavik, Iceland. hakonh@decode.is