New Possible Role of Statins in Age‐Related Diseases

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

To the Editor: Several primary and secondary prevention trials have shown that treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduces the risk for cardiovascular events (both myocardial infarction and stroke) and improves survival by reducing death rate. Other studies suggest that statin treatment may provide protection also against other age-related diseases, such as Alzheimer's disease.1 A possible explanation for these new unexpected effects is related to the pleiotropic activities of the statins, which inhibit cholesterol synthesis pathway, but also to the formation of many nonsteroidal isoprenoid compounds, vital for various cellular functions. In addition, beyond their lipid-lowering activity, due to a reduction in low-density lipoprotein-cholesterol levels, many studies have shown that statins provide important beneficial effects on endothelial function; inflammation; arterial myocyte proliferation, migration, and plaque stability; and antithrombotic effects by modulating platelet activity and coagulation process.2 Other pleiotropic effects of statins are being searched for worldwide. We focused our research on a recently discovered activity of statins, which leads to the inactivation of small G proteins and specifically of Ras p21,3 a small guanosine triphosphatase protein that controls growth and apoptosis by inhibiting the farnesylation pathway. To be functionally active, Ras p21 has to be farnesylated at a cysteine near the COOH terminus of the molecule. This lipid anchor is essential to attach the Ras protein to the internal layer of the plasma membrane and to assembly the Ras signaling cascade.4 In previous studies it was found that Ha-Ras, an isoform of Ras p21, stimulates reactive oxygen species (ROS) by activating reduced nicotinamide adenine dinucleotide phosphate oxidase complex, increasing hydrogen peroxide–induced cell death or apoptosis.5,6 The authors conducted studies to see whether treatment with statins can reduce cell and tissue oxidative injury and therefore protect the brain from age-related damage and possibly prevent the development of neurodegenerative processes, such as that occurring in Alzheimer's disease. Moreover, the same protection against oxidative damage could be expanded to stroke caused by ischemic injury. Human umbilical vein endothelial cells were stressed in vitro for 2 hours with an oxidative stressor (2 mm H2O2); in this condition, Ras p21 is fully activated. Six hours after the removal of the stimulus, apoptosis was detected in about 25% of the cells using annexin V fluorescent method.6 Overnight preincubation with 10 μm lovastatin reduced apoptosis by 92%. To test whether the effect of lovastatin was secondary to farnesylation inhibition, a permeable specific inhibitor of farnesyl transferase (FTI-277) was used. Preincubation with 20 μm FTI-277 reduced apoptosis by 97%. Because apoptosis could be reduced in vitro by inhibiting farnesylation of Ras p21, in vivo the protective effects of FTI-277 in brain injury was tested, where oxidative stress is very high. In Sprague-Dawley rats, an excitotoxic lesion was performed using an intrastriatal injection of N-methyl-d-aspartate (NMDA). The glutamate toxicity has been attributed to an influx of calcium ions through NMDA channels, which induce an increase of intracellular ROS.7 Pretreatment with FTI-277 (20 μm), also delivered by intrastriatal injection, was able to reduce significantly the damaged area when compared with controls. In brain tissue homogenate, performing a Western blot analysis with monoclonal antipan Ras antibody, it was found that FTI-277, by decreasing prenylation, causes the accumulation of nonprenylated inactive Ras in the cytosolic fraction. These findings in vivo also suggest that FTI-277 increases the tolerance of brain tissue to NMDA-induced oxidative stress via Ras pathway. These in vitro and in vivo data indicate that Ras inhibition prevents apoptosis and necrosis via a reduction of ROS. Thus, the inhibition of Ras farnesylation might account for the improved prognosis of age-related disease such as dementia, coronary heart disease, and stroke after statin treatment beyond the well-known actions on plasma cholesterol levels.