Pleiotropic effects of statins in hypercholesterolaemia: a prospective observational study using a lipoproteomic based approach

Abstract

Background: The benefit of statins in the prevention of cardiovascular disease is well founded, derived from their lipid lowering and pleiotropic effects. The concept of lipoproteins as lipid transporters has evolved to encompass functions in coagulation, inflammation, and redox reactions due to their unique protein cargo. The aim of this study was to determine the effect of statin therapy on lipoproteins and their protein cargo by use of an unbiased bottom-up proteomics approach in people with hypercholesterolaemia.

Methods: 11 people fulfilling the inclusion criteria were recruited into this UK-based single centre prospective observational study. They were started on statins for primary prevention. Blood was withdrawn at baseline and after a minimum of 2 months of statin therapy. Plasma was co-incubated with a lipoaffinity resin. Isolated proteins were digested and analysed with label-free two-dimensional liquid chromatography coupled to electrospray high-definition ion mobility tandem mass spectrometry.

Findings: 218 proteins were identified with Progenesis QI software, with 33 proteins demonstrating significant differential expression between the pre-statin and the on-statin samples (each p<0·05). 17 proteins were upregulated by statin therapy, including proteins concerned with cytoskeletal organisation (vinculin p<0·0001, tropomyosin α4 p=0·0108), antioxidative (peroxiredoxin 2 p=0·0092), and anti-inflammatory effects (transgelin-2 p=0·0071). Apolipoprotein B100 was downregulated by statin therapy, consistent with it mechanism of action (p=0·0006). Statin therapy downregulated novel proteins concerned with the modulation of pancreatic β-cell function (adipsin p=0·0056) and haemopoietic precursor proliferation (stem cell growth factor p<0·0001).

Interpretation: Our findings show that statins remodel the cytoskeletal architecture and mediate various anti-inflammatory, antioxidant, and antiproliferative effects that might limit endothelial dysfunction. The downregulation of adipsin, a novel adipokine that stimulates insulin secretion, could explain the controversial link between statin use and the development of diabetes. This study extends our understanding of the beneficial and harmful pleiotropic effects of statin therapy.

Funding: British Heart Foundation.