Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase

Abstract

Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514+/-57408 microm(2)), and descending aorta (7.0+/-1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice.

Figure 1

Analysis of SCD-1 in the livers of C57BL/6J mice receiving SCD-1 or control ASOs and exposed to CIH or IA for 10 weeks (n=6 per group). A, Hepatic SCD-1 mRNA levels by real-time RT-PCR; Ct indicates the critical threshold cycle; ΔCt is the difference between 18S and SCD Ct values. B and C, SCD-1 protein levels by immunoblot with total liver lysate. B, SCD-1 and α-actin bands in representative samples. C, Mean optical density of SCD-1 bands normalized to α-actin. Solid bars indicate CIH; open bars, IA. *P<0.05 for the difference between CIH and IA.

Figure 2

The HPLC profile of plasma cholesterol in C57BL/6J mice on a high-cholesterol diet after exposure to CIH or IA while receiving SCD-1 or control ASOs. †P<0.01, ††P<0.001 for the effect of CIH; *P<0.05, **P<0.01, ***P<0.001 for the effect of SCD-1 ASOs.

Figure 3

Representative cross-sections of the ascending aorta (sinus of Valsalva) in C57BL/6J mice exposed to IA and control ASOs injections (A), CIH and control ASOs (B), IA and SCD-1 ASOs (C), or CIH and SCD-1 ASOs (D). Transverse frozen sections of the aorta were stained with oil red O and hematoxylin. Original magnification, ×100. The thick arrow points to the distinct atherosclerotic plaque in a mouse exposed to CIH and control ASOs. The thin arrow points to the small amount of lipids in the aorta stained in red in a mouse exposed to CIH and SCD-1 ASOs.

Figure 4

Representative images of the thoracic (aortic arch and descending aorta) and abdominal aorta by the en face method in C57BL/6J mice exposed to IA and control ASO injections (A), CIH and control ASOs (B), IA and SCD-1 ASOs (C), or CIH and SCD-1 ASOs (D); Sudan IV staining; original magnification, ×10, water immersion. E, Mean area of the total aortic surface covered by atherosclerotic lesions. *P<0.05 for the difference between control ASOs and SCD-1 ASOs.

Figure 5

Relationships between nocturnal oxyhemoglobin desaturation (ΔSaO₂) and hepatic levels of SCD in patients undergoing bariatric surgery; ΔSaO₂ is a difference between baseline SaO₂ and an average nocturnal SaO₂ nadir during disordered breathing events (average low SaO₂). A, mRNA levels measured by real-time RT-PCR; Ct indicates the critical threshold cycle; ΔCt, is the difference between 18S and SCD Ct values. Each data point represents 1 patient. B, SCD protein by immunoblot. Left, SCD and α-actin bands in representative samples of patients with mild (<5%) and severe (≥5%) oxyhemoglobin desaturation. Right, Mean optical density of SCD-1 bands normalized to α-actin. Solid bars indicate ΔSaO₂ ≥5%; open bars, ΔSaO₂ <5%.

Figure 6

The HPLC profile of serum triglycerides (A) and cholesterol (B) in patients undergoing bariatric surgery separated in 2 groups based on the median value of ΔSaO₂, which is a difference between baseline nocturnal SaO₂ and average low SaO₂ during disordered breathing events. *P<0.05 and †P<0.01 for the difference between the groups.