Role of small GTPase protein Rac1 in cardiovascular diseases: development of new selective pharmacological inhibitors.

A pathway-based genome-wide association analysis has recently identified Rac1 as one of the biologically important gene in coronary heart diseases. The role of the small GTPase Rac1 in cardiac hypertrophy and atherosclerosis has also been documented in clinical studies with the HMG-CoA reductase inhibitors and in in vitro and in vivo settings using transgenic and knockout mice. Thus, Rac1 has emerged as a new pharmacological target for the treatment of cardiovascular diseases. The activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase-activating proteins. Three categories of selective Rac1 inhibitors have been developed affecting different steps of this pathway: antagonists of Rac1-guanine nucleotide exchange factor interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity. These chemical compounds have shown to selectively inhibit Rac1 activation in cultured cell lines without affecting the homologous proteins RhoA and Cdc42. Moreover, pioneer studies have been conducted with Rac1 inhibitors in in vivo experimental models of cardiovascular diseases with encouraging results. The present review summarizes the current knowledge of the role of Rac1 in cardiovascular diseases and the pharmacological approaches that have been developed to selectively inhibit its function.