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Network analysis reveals a causal role of mitochondrial gene activity in atherosclerotic lesion formation.

Abstract：

BACKGROUND AND AIMS:Mitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation. METHODS:To test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach. RESULTS:During hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses. CONCLUSIONS:Using a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes.

journal_name

Atherosclerosis

journal_title

Atherosclerosis

authors

Vilne B,Skogsberg J,Foroughi Asl H,Talukdar HA,Kessler T,Björkegren JLM,Schunkert H

doi

10.1016/j.atherosclerosis.2017.10.019

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

39-48

eissn

0021-9150

issn

1879-1484

pii

S0021-9150(17)31339-4

journal_volume

267

pub_type

杂志文章

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Network analysis reveals a causal role of mitochondrial gene activity in atherosclerotic lesion formation.