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A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation.

ABSTRACT: Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not lipid driven, thus allowing direct evaluation of putative anti-inflammatory effects. The anti-inflammatory potency of increasing doses (0, 20 or 40 mg/day) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair. A comprehensive analysis using immunohistochemistry, mRNA and protein analyses was applied on aortic wall samples collected during surgery. The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients. Both statins equally effectively and dose-dependently reduced aortic wall expression of NFκB regulated mediators (i.e. IL-6 (P<0.001) and MCP-1 (P<0.001)); shifted macrophage polarization towards a M2 phenotype (P<0.0003); selectively reduced macrophage-related markers such as cathepsin K and S (P<0.009 and 0.0027 respectively), and ALOX5 (P<0.0009), and reduced vascular wall NFκB activity (40 mg/day group, P<0.016). No effect was found on other cell types. Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth (P<0.337). Hence, in the context of AAA the clinical relevance of statins pleiotropy appears minimal.

SUBMITTER: van der Meij E

PROVIDER: S-EPMC3551939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTaiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin-angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients.MethodsOf 248,797 patients who received a hypertension diagnosis in Taiwan during 2001-2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose-response relationship, we categorized only statin or RASI use into four groups in each cohort: <28 (nonusers), 28-90, 91-365, and >365 cumulative defined daily doses (cDDDs).ResultsIn the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50-0.65), 0.72 (0.53-0.98), and 0.47 (0.41-0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54-0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used.ConclusionStatins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis risk.

Project description:Many approved drugs are pleiotropic: for example, statins, whose main cholesterol-lowering activity is complemented by anticancer and prodiabetogenic mechanisms involving poorly characterized genetic interaction networks. We investigated these using the Saccharomyces cerevisiae genetic model, where most genetic interactions known are limited to the statin-sensitive S288C genetic background. We therefore broadened our approach by investigating gene interactions to include two statin-resistant genetic backgrounds: UWOPS87-2421 and Y55. Networks were functionally focused by selection of HMG1 and BTS1 mevalonate pathway genes for detection of genetic interactions. Networks, multilayered by genetic background, were analyzed for key genes using network centrality (degree, betweenness, and closeness), pathway enrichment, functional community modules, and Gene Ontology. Specifically, we found modification genes related to dysregulated endocytosis and autophagic cell death. To translate results to human cells, human orthologues were searched for other drug targets, thus identifying candidates for synergistic anticancer bioactivity. IMPORTANCE Atorvastatin is a highly successful drug prescribed to lower cholesterol and prevent cardiovascular disease in millions of people. Though much of its effect comes from inhibiting a key enzyme in the cholesterol biosynthetic pathway, genes in this pathway interact with genes in other pathways, resulting in 15% of patients suffering painful muscular side effects and 50% having inadequate responses. Such multigenic complexity may be unraveled using gene networks assembled from overlapping pairs of genes that complement each other. We used the unique power of yeast genetics to construct genome-wide networks specific to atorvastatin bioactivity in three genetic backgrounds to represent the genetic variation and varying response to atorvastatin in human individuals. We then used algorithms to identify key genes and their associated FDA-approved drugs in the networks, which resulted in the distinction of drugs that may synergistically enhance the known anticancer activity of atorvastatin.

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A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation.

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