Coronary artery disease is the most common cause of death in the developed countries in both men and women. Multiple risk factors have been associated with an increase incidence of coronary artery disease, including hypertension, high levels of low-density lipoprotein cholesterol, and low levels of high-density lipoprotein; and since then different therapies have been developed to control these physiological parameters. Among them, the drugs affecting the mevalonate pathway, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), have shown a remarkable reduction in cardiovascular events by reducing the low-density lipoprotein-cholesterol levels.1 However, preclinical and clinical evidence suggest that the antiatherosclerotic properties of statins may not be mediated solely by their lipid-lowering properties, but possibly through the so-called pleiotropic effects.
The pleiotropic effects of statins are the results of the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which leads to subsequent reduction in nonsteroidal isoprenoid synthesis.2,3 These chemical entities are required for the post-translational isoprenylation of intracellular proteins and their membrane localization, a prerequisite event for their activity. Several isoprenylated proteins have been identified, but the pleiotropic effects of statins are considered to be mediated mainly by the inhibition of the activity of small GTP-binding proteins (eg Rho, Rac, and Ras).4,5 Thus, the basic investigation of the molecular mechanism of action of statins has led to the identification of a set of isoprenylated proteins potentially involved in cardiovascular diseases.
From these evidences, a series of experimental approaches have been pursued to define the role of small GTPases in cardiovascular diseases and their potential as pharmacological targets. In these series of review articles on “Role of small GTPases in atherogenesis: from basic science to the development of new pharmacological agents” the current knowledge on the role of small GTPases and their effectors in cardiovascular diseases is discussed. The pharmacological studies of small GTPase inhibitors conducted in in vitro and in vivo experimental models are also summarized, including the results of the clinical use of the Rho kinase inhibitor fasudil. In particular, it will be emphasized that the breakthrough in the development of selective pharmacological inhibitors of the small GTPase proteins is represented by the identification of compounds capable to interfere with the interaction between Rac and its guanine nucleotide exchange factors or effectors.6–9 Thus, the inhibition of protein–protein interaction appears to be the most promising approach for the development of selective small GTPase inhibitors, and additional compounds affecting RhoA or Cdc42 proteins could be identified and tested in the future in animal models of cardiovascular diseases. Although such inhibitors are only at preclinical development, the fact that the Rho kinase inhibitor fasudil has been approved for human use suggests the feasibility to pharmacologically modulate these intracellular pathways.
Altogether the basic pharmacological research conducted with statins, during the past three decades, has led to hypothesize the existence of the pleiotropic effects mediated by the inhibition of isoprenylated proteins and in particular the small GTPases. From these evidences, we are now facing a new era of drug development with selective small GTPase inhibitors with potential antiatherosclerotic and cardioprotective direct effects. Future studies will determine whether this approach will succeed or not.
1. Mihaylova B, Emberson J, Blackwell L, et al.. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–590.
2. Bellosta S, Ferri N, Arnaboldi L, et al.. Pleiotropic effects of statins in atherosclerosis and diabetes. Diabetes Care. 2000;23(suppl 2):B72–B78.
3. Laufs U, Liao JK. Direct vascular effects of HMG-CoA reductase inhibitors. Trends Cardiovasc Med. 2000;10:143–148.
4. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21:1712–1719.
5. Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998;279:509–514.
6. Gao Y, Dickerson JB, Guo F, et al.. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A. 2004;101:7618–7623.
7. Ferri N, Bernini KS, Corsini A, et al.. 3-Aryl-N-aminoylsulfonylphenyl-1H-pyrazole-5-carboxamides: a new class of selective Rac inhibitors. Med Chem Commun. 2013;4:537–541.
8. Ferri N, Corsini A, Bottino P, et al.. Virtual screening approach for the identification of new Rac1 inhibitors. J Med Chem. 2009;52:4087–4090.
9. Bosco EE, Kumar S, Marchioni F, et al.. Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation. Chem Biol. 2012;19:228–242.