Abstract
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up-regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta-analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin users with chronic lung diseases do not seem to be mediated through direct regulation of gene expression in the lung.
Highlights
Statins block HMG-CoA reductase (HMGCR), a rate-limiting enzyme responsible for the synthesis of endogenous cholesterol and non-sterol isoprenoids
The aim of this study was to evaluate the impact of statin treatment on gene expression in human lung in order to identify novel molecular pathways underpinning the potential benefits of statins in chronic lung diseases
We analyzed the impact of statins on gene expression in the lung in order to elucidate in humans the molecular mechanisms underpinning the clinical benefits of statins in chronic lung diseases
Summary
Statins block HMG-CoA reductase (HMGCR), a rate-limiting enzyme responsible for the synthesis of endogenous cholesterol and non-sterol isoprenoids. Statins are used predominantly to manage hypercholesterolemia and for secondary prevention to reduce the risk of cardiac events [1, 2]. Statins inhibit cholesterol-independent pathways leading to secondary or pleiotropic actions such as antioxidant [3] and anti-inflammatory [4,5,6] effects. A recent study demonstrated no effect of statin on exacerbation rates and the time to a first exacerbation in patients with moderate-to-severe COPD [28].
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