mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease.
BACKGROUND
Atherosclerotic plaque behaviour is influenced by intra-plaque inflammation, matrix turnover, and the lipid core volume. Peroxisome proliferator activated receptor gamma (PPARgamma) modulates atherosclerosis by its anti-inflammatory and anti-protease activity. PPARgamma promotes lipid efflux through the liver X receptor alpha (LXRalpha) and the ATP binding cassette transporter A1 (ABCA1). Matrix metalloproteinase 9 (MMP-9) and cyclooxygenase 2 (COX-2) are implicated in plaque instability.


OBJECTIVE
To assess the expression of these genes in occlusive and ectatic atherosclerotic disease to determine the relation between genes involved in lipid efflux and matrix degradation.


METHODS
Carotid endarterectomy specimens from 16 patients and aneurysm tissue from 16 patients undergoing abdominal aortic aneurysm repair were used. Inferior mesenteric arteries from colectomy specimens from 12 patients served as controls. Total RNA was extracted from pulverised tissue and reverse transcribed into cDNA. Quantitative real time polymerase chain reaction (PCR) was performed using fluorescently labelled probes for ABCA1, LXRalpha, PPARgamma, COX-2, and MMP-9.


RESULTS
PPARgamma expression was significantly lower in both occlusive and ecstatic atherosclerotic disease (p<0.001), whereas LXRalpha and ABCA1 expression was significantly increased (p<0.01). MMP-9 expression was significantly increased in diseased tissues (p<0.0001), and values were highest in occlusive disease (p<0.01). The increases in ABCA1 and MMP-9 mRNA were significantly correlated in diseased tissues (p<0.01, r=0.71 and r=0.78). COX-2 expression was increased in ectatic but low in occlusive disease (p<0.01).


CONCLUSIONS
This observational study suggests a role for therapeutic upregulation of PPARgamma, which could potentially upregulate lipid efflux through ABCA1 and inhibit matrix degradation through inhibition of MMP-9.
Soumian
S
S
Department of Vascular Surgery, Imperial College, Charing Cross Hospital, fulham Palace Road, London W68RF, UK. sonis@doctors.org.uk
Gibbs
R
R
Davies
A
A
Albrecht
C
C
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000368:Aged; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D000071518:Liver X Receptors; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D008565:Membrane Proteins; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020780:Matrix Metalloproteinase 9