Atorvastatin protects against deleterious cardiovascular consequences induced by chronic intermittent hypoxia

Abstract

Chronic intermittent hypoxia (IH), a major component of obstructive sleep apnea (OSA), contributes to the high risk of cardiovascular morbidity. We have previously demonstrated that IH-induced oxidative stress is involved in the hypertension and in the hypersensitivity to myocardial infarction. However, the mechanisms underlying these cardiovascular alterations are still unclear, as well as the role of potential protective treatment. Atorvastatin has pleiotropic actions, including increasing nitric oxide (NO) bioavailability and reducing inflammation and oxidative damage. The aim of this study was to evaluate the beneficial effect of a two time course of this treatment against the deleterious cardiovascular consequences of IH. Rats were divided into two groups subjected to chronic IH or normoxic (N) exposure. IH consisted of repetitive one-minute cycles (with only 30 s of a 5% inspired O2 fraction) and was applied for eight hours during daytime, for 14 (simultaneous protocol) or 28 d (delayed protocol). Atorvastatin (10 mg/kg/ d) or its vehicle was administered during the 14 d simultaneous protocol or the last 14 d of the delayed protocol. For both protocols, systolic arterial pressure was significantly increased by 14 d IH exposure. Atorvastatin prevented this deleterious effect in the simultaneous protocol. Carotid artery compliance and endothelial function were significantly altered after 28 d but not after 14 d of IH exposure. Delayed atorvastatin administration preserved these vascular parameters. IH also increased hypersensitivity to myocardial infarction after 14 d exposure, and atorvastatin abolished this deleterious effect. IH also enhanced cardiac NADPH expression and decreased aortic superoxide dismutase activity after 14 d exposure. Atorvastatin significantly restored these activities. In conclusion, whereas IH rapidly increased blood pressure, myocardial infarction hypersensitivity and oxidative stress, compliance, endothelial function and the structural wall of the carotid artery were only altered after a longer IH exposure. Atorvastatin prevented all these deleterious cardiovascular effects, leading to a potentially novel pharmacological therapeutic strategy for OSA syndrome.

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

“…Our data are consistent with the literature, which reports the following: (1) an independent association between OSA and hypertension in humans34 and (2) a determinant role of chronic IH in inducing elevation of arterial and blood pressure in healthy humans and animals exposed to IH 35, 36, 37. We further demonstrated that, in addition to the elevation of arterial blood pressure, IH also induces an arterial inflammatory remodeling with subsequent stiffening.…”

“…These data are in accordance with clinical observations, demonstrating a significant increase in the carotid artery intima‐media thickness in patients with OSA that correlates to the severity of nocturnal hypoxemia 38, 39, 41. In rodent models, exposure to at least 14 days of IH resulted in enlarged intima‐media thickness and/or disruption of the elastic network 10, 11, 12, 37, 42, 43. In addition to structural remodeling, arterial stiffness and hypertension are also under the control of endothelial‐derived mediators, such as NO,40 and reduced NO bioavailability contributes to endothelial dysfunction, which represents a hallmark of hypertension and arterial stiffening.…”

High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size

“…Recently, Buchner et al (9) demonstrated that OSA patients exhibit an increase in infarct size after an ischemic event compared with patients without OSA. Several animal studies have confirmed these clinical observations and demonstrated that IH induces an elevation of mean arterial blood pressure (BP) and increases myocardial infarct size after ischemia-reperfusion protocols (6,35,54,57,62).…”

“…21) and an increase in arterial BP (6,35,57,62). As ER stress inhibitors have been shown to prevent both ANG II-induced systemic hypertension (37) and hypoxiainduced pulmonary arterial hypertension (42) in mice, our data suggest that prolonged ER stress induced by IH could contribute to the IH-induced elevation of arterial BP.…”

Obstructive Sleep Apnoea: A Risk Factor for Hypertension

“…The other novel biomarkers discovered, having a role in developing hypertension in OSA include Nesfatin-1, Fibrinogen, and YKL-40 (also referred to as human cartilage glycoprotein) 42 . A study successfully demonstrated the protective effects of atorvastatin against deleterious effects of inflammation on cardiovascular consequences induced by chronic intermittent hypoxia using murine model 46 .…”