Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Abstract

Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

Data-analytically derived flexible HbA1c thresholds for type 2 diabetes mellitus diagnostic

“…Indeed, modus-operandi of the statin medication is to trick the metabolism into destroying free LDL particles in serum instead of recycling cholesterol in them. [74] Incidentally, this explains why statins are especially effective at early stages of CVD. Therefore, both LDL and TC are expected to fall.…”

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…Statins are widely prescribed drugs for the treatment of hypercholesterolemia and act to reduce plasma cholesterol levels by inhibiting the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methy-lglutaryl-CoA reductase. In addition to the cholesterol lowering effect, statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from excitotoxins, apoptosis, and oxidative stresses, and promoting synaptogenesis [16][17][18][19] . In particular, statins have been linked to the reduced prevalence of AD in statin-prescribed populations [20,21] , the improved cognition in normo-cholesterolemic patients [22] , and the slowed cognitive decline in mild-to-moderate AD patients [23] .…”

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

“…A recent meta-analysis by Wong et al also showed that statins have preventive effects on AD [13] . Evidence from cell culture experiments and animal studies has suggested that statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from Aβ-induced neurotoxicity, apoptosis and oxidative stress, and promoting synaptogenesis [14][15][16][17] . Recently, a transgenic mouse model of tauopathy showed a reduction in NFTs in response to statin treatment in both early and late stages of disease progression [18] .…”