title: Oxidised LDL lipids, statins and a blood-brain barrier.
abstract: Elevated cholesterol in mid-life has been associated with increased risk of dementia in later life. We have previously shown that low density lipoprotein (LDL) is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged. Increased systemic oxidative modification (oxLDL) and nitration is also observed during hypercholesterolemia. We have investigated the hypothesis that disruption of blood brain barrier (BBB) function by oxLDL and their lipids may increase risk of neurodegeneration in later life and that statin intervention can mitigate the effects of hyperlipidaemia in mid-life. LDL isolated from statin-naïve hypercholesterolaemic subjects had higher mobility by agarose gel electrophoresis (Rf;0.53±0.06) and 8-isoprostane F2α concentration (43.5±8.42pg/ml) compared to control subjects (Rf; 0.46±0.05 and 24.2±5.37pg/ml respectively; p<0.05). Compared to HMVEC treatment with the LDL-lipids (5μM) from normolipidaemic subjects, LDL-lipids from hypercholesterolaemic subjects increased barrier permeability (103.4±12.5 Ωcm2 v 66.7±7.3 Ωcm2,P<0.01) and decreased cellular glutathione levels (18.5nmol/mg v 12.3nmol/mg) compared to untreated cells (26.2±3.6nmol/mg). LDL-lipids isolated from normolipidaemic subjects shows reduced risk to damage a BBB model compared with LDL-lipids from hypercholesterolaemic subjects. Moreover, a three month statin-intervention reduced the propensity for LDL-lipids from subjects with hyperlipidaemia to damage HMVEC. Post-statin treatment the cytotoxic and pro-inflammatory effects of LDL lipids disappeared. These data support the hypothesis that in vivo intervention with statins modifies LDL lipid oxidation, exerting a protective effect against in microvascular damage independent of cholesterol concentration.
authors.affiliation: Aston University (ARCHA), Life and Health Sciences, UK. Electronic address: h.r.griffiths@aston.ac.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffiths
authors.affiliation: Aston University (ARCHA), Life and Health Sciences, UK.
authors.forename: Dias
authors.initials: D
authors.lastname: Irundika
authors.affiliation: City Hospital (Birmingham), Cardiovascular, UK.
authors.forename: Gyh
authors.initials: G
authors.lastname: Lip
authors.affiliation: Aston University (ARCHA), Life and Health Sciences, UK.
authors.forename: Corinne
authors.initials: C
authors.lastname: Spickett
authors.affiliation: University of Cologne (Cologne), Institute of Geriatrics, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Polidori