Belaidi Elise, Joyeux-Faure Marie, Ribuot Christophe, Launois Sandrine H, Levy Patrick, Godin-Ribuot Diane
INSERM, Grenoble, France.
J Am Coll Cardiol. 2009 Apr 14;53(15):1309-17. doi: 10.1016/j.jacc.2008.12.050.
Our aim was to investigate the involvement of the endothelin (ET) system in the cardiovascular consequences of intermittent hypoxia (IH).
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.
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.
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.
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.
我们的目的是研究内皮素（ET）系统在间歇性低氧（IH）所致心血管后果中的作用。
阻塞性睡眠呼吸暂停（OSA）综合征是心血管疾病发病的重要危险因素。慢性IH是OSA的主要组成部分，被认为是OSA期间发生的大多数心血管并发症的原因，但潜在机制仍有待确定。
对易患高血压的大鼠（自发性高血压大鼠[SHR]）及其血压正常的对照大鼠施加慢性IH。在体内和Langendorff灌注心脏中评估心血管效应。使用组织染色质免疫沉淀、酶联免疫吸附测定、免疫染色和蛋白质印迹法研究缺氧诱导因子（HIF）-1活性、心肌ET-1基因的靶向作用以及ET系统的激活。
与对照大鼠相比，慢性IH增强了SHR的高血压发展和梗死面积。这伴随着心肌大ET-1、ET-1和ET-A受体表达的增加，并且仅在SHR中增强了冠状动脉对ET-1的血管反应性。心肌HIF-1活性增加，并且仅在慢性IH后显示HIF-1与心肌ET-1基因的启动子相关联。此外，在慢性IH期间给予波生坦（一种混合ET受体拮抗剂）可预防血压升高和梗死面积增加。
在SHR中，由HIF-1活性介导的ET系统激活导致对慢性IH的易感性增加及其相关的心血管后果，从而导致高血压和缺血性损伤。此外，波生坦的有益作用表明探索ET拮抗剂作为OSA可能的治疗工具。
