Chemokines as potential therapeutic targets in atherosclerosis.
Atherosclerosis is a chronic disease with high morbidity and mortality around the globe. It is characterized by chronic inflammation of the vessel wall, which is perpetuated by the continuous migration of cells to and within the atherosclerotic lesion. Chemokines (CK) and chemokine receptors (CKR) together with other chemoattractants and adhesion molecules are major mediators facilitating this process. Many CK/CKR (CC, CX3C and CXC) and other chemoattractants (e.g. leukotrienes) have been implicated in atherogenesis, but only a few have been validated as pathogenic by in vitro assays, in vivo experiments using gene-targeted animal models and genetic studies. Promising attempts are currently made to inhibit CK-dependent cell recruitment to lesion by using neutralizing antibodies, mutant proteins, viral and synthetic inhibitors or receptor antagonists. Some of the therapeutics have already entered clinical trials for other conditions and are about to be tested in human atherosclerosis. However, our limited understanding of the complex CK system and the functional specialization of individual CK/CKR, translatability of animal research into human population, limitations of current imaging techniques and surrogate markers for evaluation of the benefits of potential anti-CK compounds are still hampering therapeutic exploitation of the CK system in atherosclerosis. Hopefully we will be able to solve many of these issues in the near future and use this approach to control atherosclerotic disease in man.