Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis.
Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.
U1042, Grenoble.
Elodie
E
Gautier-Veyret
Claire
C
Arnaud
Magnus
M
Bäck
Jean-Louis
JL
Pépin
Marcelo H
MH
Petri
Jean-Philippe
JP
Baguet
Renaud
R
Tamisier
Patrick
P
Lévy
Françoise
F
Stanke-Labesque
D000328:Adult; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D015992:Body Mass Index; D001835:Body Weight; D016022:Case-Control Studies; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006400:Hematocrit; D006801:Humans; D000860:Hypoxia; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D012307:Risk Factors; D020181:Sleep Apnea, Obstructive / Q000473:pathology; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
D001057:Apolipoproteins E; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; C115461:SC 560; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D051545:Cyclooxygenase 1