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PRE-CLINICAL RESEARCH

Major Role for Hypoxia Inducible Factor-1 and the Endothelin System in Promoting Myocardial Infarction and Hypertension in an Animal Model of Obstructive Sleep Apnea

Elise Belaidi, PhD^_*, Marie Joyeux-Faure, PhD^_*,, Christophe Ribuot, PhD^_*,, Sandrine H. Launois, MD, PhD^_*,,, Patrick Levy, MD, PhD^_*,, and Diane Godin-Ribuot, PhD^_*,,_*

^_* INSERM, Grenoble, France
Université Joseph Fourier, Faculté de Médecine-Pharmacie, Grenoble, France
CHU de Grenoble, Hôpital A. Michallon, Laboratoire EFCR, Grenoble, France

Manuscript received May 6, 2008; revised manuscript received December 12, 2008, accepted December 15, 2008.

^_* Reprint requests and correspondence: Prof. Diane Godin-Ribuot, Laboratoire HP2, INSERM ERI017, Université Joseph Fourier, Institut Jean Roget, BP 170, 38042 Grenoble Cedex 9, France (Email: diane.ribuot{at}ujf-grenoble.fr).

Objectives: Our aim was to investigate the involvement of the endothelin (ET) system in the cardiovascular consequences of intermittent hypoxia (IH).

Background: Obstructive sleep apnea (OSA) syndrome is an important risk factor for cardiovascular morbidity. Chronic IH, a major component of OSA, is thought to be responsible for most of the cardiovascular complications occurring during OSA, but the underlying mechanisms remain to be determined.

Methods: Chronic IH was applied in rats genetically prone to develop hypertension (spontaneous hypertensive rats [SHR]) and their normotensive controls. The cardiovascular effects were assessed in vivo and in Langendorff perfused hearts. Hypoxia inducible factor (HIF)-1 activity and targeting of the myocardial ET-1 gene and activation of the ET system were investigated using tissue chromatin immunoprecipitation, enzyme-linked immunoadsorbent assay, immunostaining, and Western blotting.

Results: Chronic IH enhanced hypertension development and infarct size in SHR compared with that seen in control rats. This was accompanied by an increase in myocardial big ET-1, ET-1, and ET-A receptor expression and by an enhanced coronary vascular reactivity to ET-1 in SHR only. Myocardial HIF-1 activity was increased, and HIF-1 was shown to be linked to the promoter of the myocardial ET-1 gene after chronic IH only. Moreover, administration of bosentan, a mixed ET receptor antagonist, during chronic IH prevented both the increase in blood pressure and in infarct size.

Conclusions: In SHR, activation of the ET system, mediated by HIF-1 activity, is responsible for the enhanced susceptibility to chronic IH and for its associated cardiovascular consequences leading to hypertension and ischemic injury. Furthermore, the beneficial effects of bosentan suggest exploring ET antagonists as possible therapeutic tools in OSA.

Key Words: obstructive sleep apnea • myocardial infarction • hypoxia inducible factor-1 • gene expression • endothelin

Abbreviations and Acronyms   CPAP = continuous positive airway pressure   ET = endothelin   HIF = hypoxia-inducible factor   HRE = hypoxia response element   IH = intermittent hypoxia   MABP = mean arterial blood pressure   N = normoxia   OSA = obstructive sleep apnea syndrome   PCR = polymerase chain reaction   SHR = spontaneous hypertensive rats   WKY = Wistar Kyoto rats

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