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Pleiotropic effects of statins in hypercholesterolaemia: a prospective observational study using a lipoproteomic based approach
Poster Abstracts
Pleiotropic effects of statins in hypercholesterolaemia: a prospective observational study using a lipoproteomic based approach Sanjay Bhandari, Pankaj Gupta, Paulene Quinn, Jatinderpal Sandhu, Amirmansoor Hakimi, Donald Jones, Leong Ng
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 Blood was withdrawn at baseline and after a minimum of 2 months of statin therapy.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. Contributors SB was involved with study design, sample preparation, mass spectroscopy and data analysis, and writing of the abstract. PG was responsible for study design, patient recruitment, and sample collection. PQ, JS, AH conducted mass spectroscopy analysis. DJ was involved with mass spectroscopy and data analysis, and writing of the abstract. LN was involved with study design, data analysis, and writing of the abstract.
Published Online February 26, 2015 Poster 46 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (S Bhandari MBChB, P Quinn MPhil, J Sandhu MPhil, A Hakimi PhD, Prof L Ng MD, D Jones PhD, P Gupta MBBS); NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, UK (S Bhandari, P Quinn, J Sandhu, A Hakimi, D Jones, Prof L Ng); Department of Chemical Pathology, University Hospitals of Leicester NHS Trust, Leicester, UK (P Gupta); and Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, University of Leicester, Leicester, UK (D Jones) Correspondence to: Dr Sanjay Bhandari, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK sanjay1bhandari@ hotmail.com
Declaration of interests We declare no competing interests.
www.thelancet.com
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Pleiotropic effects of statins in hypercholesterolaemia: a prospective observational study using a lipoproteomic based approach Sanjay Bhandari, Pankaj Gupta, Paulene Quinn, Jatinderpal Sandhu, Amirmansoor Hakimi, Donald Jones, Leong Ng
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. Contributors SB was involved with study design, sample preparation, mass spectroscopy and data analysis, and writing of the abstract. PG was responsible for study design, patient recruitment, and sample collection. PQ, JS, AH conducted mass spectroscopy analysis. DJ was involved with mass spectroscopy and data analysis, and writing of the abstract. LN was involved with study design, data analysis, and writing of the abstract.
Published Online February 26, 2015 Poster 46 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (S Bhandari MBChB, P Quinn MPhil, J Sandhu MPhil, A Hakimi PhD, Prof L Ng MD, D Jones PhD, P Gupta MBBS); NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, UK (S Bhandari, P Quinn, J Sandhu, A Hakimi, D Jones, Prof L Ng); Department of Chemical Pathology, University Hospitals of Leicester NHS Trust, Leicester, UK (P Gupta); and Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, University of Leicester, Leicester, UK (D Jones) Correspondence to: Dr Sanjay Bhandari, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK sanjay1bhandari@ hotmail.com
Declaration of interests We declare no competing interests.
www.thelancet.com
21