title: Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice.
abstract: Patients with obstructive sleep apnea, who experience episodic hypoxia and hypercapnia during sleep, often demonstrate increased inflammation, oxidative stress, and dyslipidemia. We hypothesized that sleep apnea patients would be predisposed to the development of atherosclerosis. To dissect the mechanisms involved, we developed an animal model in mice whereby we expose mice to intermittent hypoxia/hypercapnia (IHH) in normobaric environments. Two- to three-month-old low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were fed a high-fat diet for 8 or 16 wk while being exposed to IHH for either 10 h/day or 24 h/day. Plasma lipid levels, pulmonary artery and aortic atherosclerotic lesions, and cardiac function were then assayed. Surprisingly, atherosclerosis in the aorta of IHH mice was similar compared with controls. However, in IHH mice, atherosclerosis was markedly increased in the trunk and proximal branches of the pulmonary artery of exposed mice; even though plasma cholesterol and triglycerides were lower than in controls. Hemodynamic analysis revealed that right ventricular maximum pressure and isovolumic relaxation constant were significantly increased in IHH exposed mice and left ventricular % fractional shortening was reduced. In conclusion, 1) Intermittent hypoxia/hypercapnia remarkably accelerated atherosclerotic lesions in the pulmonary artery of Ldlr(-/-) mice and 2) increased lesion formation in the pulmonary artery was associated with right and left ventricular dysfunction. These findings raise the possibility that patients with obstructive sleep apnea may be susceptible to atherosclerotic disease in the pulmonary vasculature, an observation that has not been previously recognized.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Douglas
authors.forename: Karen
authors.initials: K
authors.lastname: Bowden
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pattison
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Peterson
authors.forename: Joseph
authors.initials: J
authors.lastname: Juliano
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Erika
authors.initials: E
authors.lastname: Alvarez
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imamura
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Li
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000502:physiology; D006935:Hypercapnia / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000097:blood / Q000378:metabolism / Q000473:pathology; D014280:Triglycerides / Q000097:blood; D018754:Ventricular Dysfunction / Q000097:blood / Q000378:metabolism / Q000473:pathology*
chemical_list: D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol
keywords: atherosclerosis; hemodynamics; hypertension; intermittent hypoxia and hypercapnia; obstructive sleep apnea; pulmonary artery