Akat Fırat, Fıçıcılar Hakan, Durak Ayşegül, Tuncay Erkan, Dursun Ali Doğan, Topal Çelikkan Ferda, Sabuncuoğlu Bizden, Turan Belma, Baştuğ Metin
Department of Physiology, Faculty of Medicine, Ankara University; Ankara-Turkey.
Anatol J Cardiol. 2018 Apr;19(4):259-266. doi: 10.14744/AnatolJCardiol.2018.00236.
Depressed mechanical activity is a marked complication in diabetics. Hypoxia has properties for novel diagnostic and therapeutic strategies, while intermittent hypoxia (IH) provides early functional and histologic remodeling, including some cardio benefits in early hemodynamic alterations with histologic remodeling and delayed changes in peripheral vasoreactivity. Therefore, we aimed to examine whether IH application presents a cardioprotective effect, via stabilization of hypoxia-inducible factor (HIF) in streptozotocin (STZ)-induced diabetic rat heart.
Male 10-week-old Wistar rats were randomly assigned as control group (C), IH group, (STZ)-induced diabetic group (DM) and IH applied DM group (DM+IH). Diabetes duration was kept 6 weeks and IH groups were exposed to hypobaric hypoxia at about 70 kPa (including ~14% PO2; 6 h/day for 6-weeks).
Depressed left ventricular developed pressure (LVDP) and prolonged contraction and relaxation of Langendorff-perfused hearts, as well as increased total oxidative status from streptozotocin (STZ)-induced diabetic rats were markedly prevented with IH application. IH application induced significant increase in protein expression levels of both HIF-1α and vascular endothelial growth factor (VEGF), in both control and diabetic rat hearts, whereas there were significant decreases in the protein levels of prolyl-4 hydroxylase domain enzymes, PHD2, and PHD3 in diabetic hearts. Furthermore, IH application induced marked increases in protein levels of matrix metalloproteinases, MMP-2 and MMP-9 and capillary density in left ventricle of diabetic rats.
Overall, we presented how IH application has a beneficial cardiovascular remodeling effect in left ventricular function of diabetic rats, at most, via affecting increased oxidative stress and HIF-VEGF related angiogenesis, providing information on hyperglycemia associated new targets and therapeutic strategies.
机械活性降低是糖尿病患者的一种显著并发症。缺氧具有用于新型诊断和治疗策略的特性，而间歇性缺氧（IH）可引起早期功能和组织学重塑，包括在早期血流动力学改变伴组织学重塑以及外周血管反应性延迟变化方面的一些心脏益处。因此，我们旨在研究应用IH是否通过稳定链脲佐菌素（STZ）诱导的糖尿病大鼠心脏中的缺氧诱导因子（HIF）而呈现心脏保护作用。
将10周龄雄性Wistar大鼠随机分为对照组（C）、IH组、STZ诱导的糖尿病组（DM）和应用IH的糖尿病组（DM+IH）。糖尿病病程维持6周，IH组暴露于约70 kPa的低压缺氧环境（包括~14%的氧分压；每天6小时，持续6周）。
应用IH可显著预防STZ诱导的糖尿病大鼠左心室发育压力（LVDP）降低、Langendorff灌注心脏的收缩和舒张延长以及总氧化状态增加。在对照和糖尿病大鼠心脏中，应用IH均显著诱导HIF-1α和血管内皮生长因子（VEGF）蛋白表达水平升高，而糖尿病心脏中脯氨酰-4羟化酶结构域酶PHD2和PHD3的蛋白水平显著降低。此外，应用IH可显著诱导糖尿病大鼠左心室基质金属蛋白酶MMP-2和MMP-9的蛋白水平以及毛细血管密度增加。
总体而言，我们展示了应用IH如何最多通过影响氧化应激增加和HIF-VEGF相关血管生成，对糖尿病大鼠左心室功能产生有益的心血管重塑作用，为高血糖相关的新靶点和治疗策略提供了信息。
