Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia

Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 4.01). 03/2011; 300(4):H1467-76. DOI: 10.1152/ajpheart.00604.2009
Source: PubMed

ABSTRACT Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

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    ABSTRACT: Chronic intermittent hypoxia (CIH) in animal models has been shown to result in hypertension and elevation of sympathetic nervous system activity. Sympathetic mediated vasoconstriction is believed to be the primary mechanism underpinning CIH induced hypertension, however the potential contribution of the heart is largely overlooked. We sought to determine the contribution of cardiac output (CO) and lumbar sympathetic control of the hindlimb circulation to CIH induced hypertension. Male Wistar rats (n = 64) were exposed to 2 weeks of CIH (90s hypoxia (5% O2 nadir)/210s normoxia cycles) or normoxia for 8 hours/day. Under urethane anaesthesia, CIH treated animals developed hypertension (81.4±2.2 versus 91.6±2.4 mmHg; p<0.001), tachycardia (397±8 versus 445±7 bpm; p<0.001) and an increased haematocrit (42.4± 0.4 versus 45.0±0.4%; p<0.001). Echocardiography revealed that CIH exposure increased the CO (19.3±1.7 versus 25.8±2.6 ml/min/100g; p = 0.027) with no change in TPR (4.93±0.49 versus 4.17±0.34 mmHg/ml/min; p = 0.123). Sympathetic ganglionic blockade revealed that sympathetic control over blood pressure was not different (-27.7±1.6 versus -32.3±2.9 mmHg; p = 0.095) and no chronic vasoconstriction was found in the hindlimb circulation of CIH animals (39.4±2.5 versus 38.0±2.4 μl/min/mmHg; p = 0.336). Lumbar sympathetic control over the hindlimb circulation was unchanged in CIH animals (p = 0.761), although hindlimb arterial sympathetic density was increased (p = 0.012) and vascular sensitivity to phenylephrine was blunted (p = 0.049). We conclude that increased CO is sufficient to explain the development of CIH induced hypertension which may be an early adaptive response to raise O2 flow. We propose that sustained elevated cardiac work may ultimately lead to heart failure.This article is protected by copyright. All rights reserved
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    ABSTRACT: Background Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity. Design Thirty adult (8-10 wks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12 hours a day and fed either a high fat (HF) or a low fat control diet (CD) for 6 weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR. Results Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (Emax: HFIH 78 ± 2%, p<0.0001) when compared to the other groups (Emax: HFIA 95 ± 0.7%, CDIH 94 ± 2%, CDIA 97 ± 1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (Emax: HFIH: 179 ± 10% vs. HFIA: 149 ± 11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68 ± 0.04 vs. 0.41 ± 0.03μM, p<0.05) but were greatest in the HFIH group (0.83 ± 0.08μM, p<0.05). However, there was no significant increase in MDA levels in the HFIA group (0.45 ± 0.03μM. p = NS) when compared to all other groups. Similar effects were observed with CRP levels; CRP levels were significantly higher in the CDIH group compared with intermittent air (10.39 ± 0.38 vs. 8.70 ± 0.21μg/ml, p<0.05) but the HFIH had the greatest levels of CRP (11.87 ± 0.31μg/ml, p<0.05) In the HFIA group, CRP levels were not elevated (9.96 ± 0.37μg/ml, p=NS). Nevertheless, total antioxidant capacity and eNOS gene expression were not significantly different in the groups. Conclusion CIH caused endothelial dysfunction in mice fed an obesogenic diet. Inflammation and oxidative stress were increased in CIH and an obesogenic diet exacerbated these effects.
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