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Cellular mechanisms in intermittent hypoxia-induced cardiac damage in vivo

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Abstract

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH) during sleep, is increasingly recognized as an independent risk factor of cardiovascular diseases. OSA is associated with changes in the levels of circulating oxidative stress/inflammatory markers and dyslipidemia, supporting their mediating roles in cardiovascular pathogenesis. Our aims were to investigate the effect of IH on heart tissue using an IH-exposed rat model and to explore the potential mechanisms involved in the occurrence of cardiac damage. Male Sprague–Dawley rats were exposed to IH and intermittent normoxia as control and sacrificed after 2 or 4 weeks. IH for 4 weeks caused elevation in serum malondialdehyde and cytokine-induced neutrophil chemoattractant-1 and reduction in serum adiponectin levels. In contrast, cardiac oxidative stress and pro-inflammatory markers were suppressed while cardiac adiponectin and cholesterol levels were elevated after IH exposure for 4 weeks. In parallel, there was an increase in apoptosis in the heart of IH-exposed rats, demonstrated by elevations of Bax and cleaved caspase-3 protein and TUNEL staining. Cardiac damage was further evident with decreased arterial vessel and capillary densities, increased cardiac fibrosis, and the loss of troponin I. Our data demonstrated that IH exposure paradoxically caused systemic oxidative and inflammatory responses and cardioprotective responses, i.e., anti-oxidative and anti-inflammatory responses. Despite such a local compensatory protective mechanism, cardiac damage was observed that might be due to IH-induced cholesterol accumulation in the heart and caspase-dependent apoptosis.

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Abbreviations

BMI:

Body mass index

CO:

Carbon monoxide

CVDs:

Cardiovascular diseases

CPAP:

Continuous positive airway pressure

Nrf2:

Erythroid 2-related factor

HO-1:

Heme oxygenase-1

HDL:

High-density lipoprotein

IL-6:

Interleukin-6

IH:

Intermittent hypoxia

Keap-1:

Kelch-like ECH-associated protein

LDL:

Low-density lipoprotein

MDA:

Malondialdehyde

ROS:

Reactive oxygen species

SMA:

Smooth muscle actin

TNF-α:

Tumor necrosis factor-α

vWF:

von Willebrand factor

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Acknowledgments

This work was supported by Hong Kong Research Grant Council General Research Fund (RGC GRF) 2008–2009 (HKU 771908M).

Conflict of interest

The authors report no conflicts of interest.

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Author notes

  1. Qian Han

    Present address: Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical College, 151 Yan Jiang Road, Guangzhou, China

Authors and Affiliations

  1. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Qian Han, Sze C. Yeung, Mary S. M. Ip & Judith C. W. Mak

  2. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Judith C. W. Mak

  3. Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China

    Mary S. M. Ip & Judith C. W. Mak

  4. Room L8-40, Laboratory Block, LKS Faculty of Medicine Building, The University of Hong Kong, 21 Sassoon Road, Hong Kong SAR, China

    Judith C. W. Mak

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  1. Qian Han
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  2. Sze C. Yeung
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Correspondence to Judith C. W. Mak.

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Han, Q., Yeung, S.C., Ip, M.S.M. et al. Cellular mechanisms in intermittent hypoxia-induced cardiac damage in vivo. J Physiol Biochem 70, 201–213 (2014). https://doi.org/10.1007/s13105-013-0294-z

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  • DOI: https://doi.org/10.1007/s13105-013-0294-z

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