Concept: Mevalonate pathway
Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.
In this paper, we propose a class of multivariate random effects models allowing for the inclusion of study-level covariates to carry out meta-analyses. As existing algorithms for computing maximum likelihood estimates often converge poorly or may not converge at all when the random effects are multi-dimensional, we develop an efficient expectation-maximization algorithm for fitting multi-dimensional random effects regression models. In addition, we also develop a new methodology for carrying out variable selection with study-level covariates. We examine the performance of the proposed methodology via a simulation study. We apply the proposed methodology to analyze metadata from 26 studies involving statins as a monotherapy and in combination with ezetimibe. In particular, we compare the low-density lipoprotein cholesterol-lowering efficacy of monotherapy and combination therapy on two patient populations (naïve and non-naïve patients to statin monotherapy at baseline), controlling for aggregate covariates. The proposed methodology is quite general and can be applied in any meta-analysis setting for a wide range of scientific applications and therefore offers new analytic methods of clinical importance. Copyright © 2012 John Wiley & Sons, Ltd.
Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods.
We have previously reported that chronic oral treatment with the HMG-CoA reductase inhibitor lovastatin shows cardioprotection but interacts with the cardioprotective effect of postconditioning and that farnesol, a key intermediate of the mevalonate pathway, is cardioprotective possibly via enhancement of protein geranylgeranylation. Here we studied the interaction of the HMG-CoA reductase inhibitor atorvastatin and farnesol with postconditioning. Male Wistar rats were orally treated with vehicle (2.5% methylcellulose), 10 mg/kg/day atorvastatin, 1 mg/kg/day farnesol, or their combination, respectively, for 12 days. At the end of the treatments, hearts were isolated and perfused according to Langendorff. Hearts were subjected to 30 minutes of coronary occlusion and 120 minutes of reperfusion with or without a postconditioning protocol induced by six intermittent periods of ischemia/reperfusion of 10-s duration each. At the end of the perfusion protocol, infarct size was determined by standard triphenyltetrazolium chloride staining and expressed as % of the area at risk. We found that postconditioning significantly decreased infarct size (19.5±4.1% vs. 40.0±2.9%, p<0.05). Atorvastatin pretreatment significantly decreased infarct size (17.7±2.9%, p<0.05), however, atorvastatin inhibited the cardioprotective effect of postconditioning (40.4±2.9%). Farnesol alone significantly decreased infarct size (22.3±3.9%, p<0.05), however, it also inhibited cardioprotection by postconditioning (41.5±6.9%). The combination of atorvastatin and farnesol did not show protection (39.3±6.3%), however, their combination with postconditioning was again protective (19.9±3.7%, p<0.05). These results show that the mevalonate pathway plays a complex role in ischemia/reperfusion injury and cardioprotection by postconditioning, however, the cellular mechanism of the observed effects of atorvastatin and farnesol needs further investigation.
Contrast induced nephropathy (CIN) is a common complication of coronary angiography/angioplasty. Prevention is the key to reduce the incidence of CIN and it begins with appropriate pre-procedural management. Statins have been shown to possess pleiotropic effects (anti-oxidant, anti-inflammatory and anti-thrombotic properties) and their effects on CIN were assessed in several studies with conflicting results. Aim of this meta-analysis is to evaluate the efficacy of short-term statins for the prevention of CIN in patients undergoing coronary angiography/percutaneous interventions. We performed formal searches of PubMed, EMBASE, Cochrane central register of controlled trials and major international scientific session abstracts from January 1990 to January 2014 of trials which compares short-term statins versus Placebo for the prevention of CIN in patients undergoing coronary angiography/angioplasty. Data regarding study design, statin dose, inclusion/exclusion criteria, number of patients, and clinical outcome was extracted by 2 investigators. Eight trials were included, with a total of 4734 patients. CIN occurred in 79/2,358 patients (3.3 %) treated with statins versus 153/2,376 patients (6.4 %) of the placebo group [OR 95 % CI 0.50 (0.38-0.66), p < 0.00001; p het = 0.39]. Benefits were both observed with high-dose short-term statins [OR 95 % CI 0.44 (0.30-0.65), p < 0.0001; p het = 0.16] and low-dose statins, [OR 95 % CI 0.58 (0.39-0.88), p = 0.010; p het = 0.90]. By meta-regression analysis, no significant relationship was observed between benefits from statin therapy and patient's risk profile (p = 0.26), LDL cholesterol (p = 0.4), contrast volume (p = 0.94) or diabetes rate (p = 0.38). This meta-analysis showed that among patients undergoing coronary angiography/percutaneous intervention the use of short-term statins reduces the incidence of CIN, and therefore is highly recommended even in patients with low LDL-cholesterol levels.
Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
The mevalonate pathway is essential in eukaryotes and responsible for a diversity of fundamental synthetic activities. 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the pathway and is targeted by the ubiquitous statin drugs to treat hypercholesterolemia. Independent reports have indicated the cidal effects of statins against the flatworm parasite, S. mansoni, and the possibility that SmHMGR is a useful drug target to develop new statin-based anti-schistosome therapies. For six commercially available statins, we demonstrate concentration- and time-dependent killing of immature (somule) and adult S. mansoni in vitro at sub-micromolar and micromolar concentrations, respectively. Cidal activity trends with statin lipophilicity whereby simvastatin and pravastatin are the most and least active, respectively. Worm death is preventable by excess mevalonate, the product of HMGR. Statin activity against somules was quantified both manually and automatically using a new, machine learning-based automated algorithm with congruent results. In addition, to chemical targeting, RNA interference (RNAi) of HMGR also kills somules in vitro and, again, lethality is blocked by excess mevalonate. Further, RNAi of HMGR of somules in vitro subsequently limits parasite survival in a mouse model of infection by up to 80%. Parasite death, either via statins or specific RNAi of HMGR, is associated with activation of apoptotic caspase activity. Together, our genetic and chemical data confirm that S. mansoni HMGR is an essential gene and the relevant target of statin drugs. We discuss our findings in context of a potential drug development program and the desired product profile for a new schistosomiasis drug.
- Arteriosclerosis, thrombosis, and vascular biology
- Published over 3 years ago
Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated.
The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway’s enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPRmt, can protect yeast,C. elegans,and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins. The mechanistic basis for this protection, however, remains unknown. UsingC. elegans, we found that the UPRmtdoes not directly affect the levels of the statin target HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway in mammals. Instead, inC. elegansthe UPRmtupregulates the first dedicated enzyme of the pathway, HMG-CoA synthase (HMGS-1). A targeted RNAi screen identified two UPRmttranscription factors, ATFS-1 and DVE-1, as regulators of HMGS-1. A comprehensive analysis of the pathway’s enzymes found that, in addition to HMGS-1, the UPRmtupregulates enzymes involved with the biosynthesis of electron carriers and geranylgeranylation intermediates. Geranylgeranylation, in turn, is requisite for the full execution of the UPRmtresponse. Thus, the UPRmtacts in at least three coordinated, compensatory arms to upregulate specific branches of the mevalonate pathway, thereby alleviating mitochondrial stress. We propose that statin-mediated inhibition of the mevalonate pathway blocks this compensatory system of the UPRmtand consequentially impedes mitochondrial homeostasis. This effect is likely one of the principal bases for the adverse side effects of statins.