Abstract 13089: Evidence That Loss of Nuclear-Encoded Mitochondrial Gene Activity in the Arterial Wall Relates to Atherosclerotic Lesion Development
Introduction: Besides acting as “power houses” of the cell, mitochondria also serve as sensors of their local environment and are intimately involved in cellular defense.
Hypothesis: Dysregulation of nuclear-encoded mitochondrial (NEM) genes might represent an intermediate step by which hypercholesterolemia imposes the development of atherosclerotic lesions.
Methods and Results: In order to test this hypothesis, we examined the transcriptome of the aorta in Ldlr–/–Apob100/100Mttpflox/floxMx1-Cre at 10 week intervals by applying a number of in silico systems biology strategies. In parallel to the rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age, we observed that NEM genes were 4-fold down-regulated compared to all other genes (P=6.1x10–72). This down-regulation involved PGC1-α and -β, two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators. In addition, when studying the correlation of gene co-expression modules with mouse phenotypic traits, we identified two NEM gene-enriched modules as being the most negatively associated with changes in atherosclerotic lesion size (r= -0.42 and -0.43, P=0.04). Within these two modules, gene-set enrichment analysis revealed significant over-representation of transcription factor estrogen related receptor (ERR) α binding sites, ROS-sensitive genes, as well as several mitochondrial biogenesis-related signaling pathways. ERR-α is a known effector of PGC1 in the control of mitochondria biogenesis and antioxidant defense and, in our data, its expression tightly correlated with that of PGC1 factors. Further- more, human data revealed that both modules demonstrated significant enrichment for CAD GWAS SNPs associated with arterial wall (3.3-fold P<6.1x10–19) and blood (1.4-fold, P<8.1x10–9) gene expression, implying a causative role in atherosclerosis development. Finally, genetic lowering of plasma cholesterol at 30 weeks resulted in 4-fold up-regulation of NEM genes in the aorta of MttpΔ/Δ mice (P=3.9x10–16).
Conclusions: The arterial wall in mice responds to hypercholesterolemia by a coordinated and reversible down-regulation of NEM genes which affects atherosclerosis development.
Author Disclosures: B. Vilne: None. J. Skogsberg: None. H. Foroughi Asl: None. T. Kessler: None. J.L. Björkegren: Ownership Interest; Modest; Johan L.M. Björkegren is the founder, main shareholder, and chairman of the board for Clinical Gene Networks (CGN). H. Schunkert: None.
- © 2016 by American Heart Association, Inc.