Mitochondrial function in human atherosclerotic plaques and effects of atherogenic lipids on vascular smooth muscle cells. (23rd February 2017)

• Record Type: Journal Article
• Authors: Reinhold, Johannes; Uryga, Anna K; Murphy, Michael P; Bennett, Martin R
• Is Part Of: Lancet. Volume 389(2017)Supplement 1
• Page Start: S82
• Publication Date: 2017-02-23
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Medicine; Electronic journals; Periodicals; 610.5
• DOI: 10.1016/S0140-6736(17)30478-6
• Languages: English
• ISSNs: 0140-6736

Abstract

Abstract: Background: Mitochondrial DNA damage has been implicated in atherosclerosis but whether it is sufficient to induce mitochondrial dysfunction is unclear. Here we investigated the bioenergetics of human atherosclerotic plaques and the effects of atherogenic lipids on mitochondrial respiration and turnover in vascular smooth muscle cells (VSMCs). Methods: Human atherosclerotic plaques derived from patients undergoing carotid endarterectomy were dissected into defined regions including healthy media, shoulder region, fibrous cap, and core. Their bioenergetic profiles were investigated with an extracellular flux analyser (Seahorse, Agilent Technologies, Santa Clara, CA, USA). VSMCs derived from rat or human aortas were treated with oxidised LDL (OxLDL) before extracellular flux analysis and assessment of mitophagy using the mitochondrially targeted keima reporter. Findings: The basal oxygen consumption rate was similar across human atherosclerotic regions (five plaques, 25 samples per region). However, respiration after uncoupling with p -(tri-fluromethoxy)phenyl-hydrazone (FCCP) was significantly induced in the healthy media (mean 210% of baseline [SD 53], p=0·0017) and shoulder region (169% [47], p=0·0048) but not in the diseased fibrous cap (128% [43], p=0·15) or core (127% [32], p=0·10) regions. OxLDL decreased basal respiration in a dose-dependent manner (OxLDL at 100 μg/mL concentration mean 7·0 pmol/min per μg protein [SD 2·17] vs control 10·10 [2·86], p<0·0001), and FCCP induced respiration of rat VSMCs (8·60 [3·37] vs 14·10 [5·21], p<0·0001) and induced mitophagy in human VSMCs (0·43 arbitrary units [0·20] vs 0·15 [0·18], p=0·0007). Interpretation: We show that mitochondrial damage in human atherosclerotic plaques is sufficient to affect their function. Atherogenic lipids cause changes in mitochondrial metabolism and induce mitophagy in human VSMCs. Knowledge of the role of mitochondrial bioenergetics and turnover is important for our understanding of disease progression and could lead to future therapeutic targets. Funding: Wellcome Trust, British Heart Foundation, Medical Research Council.