Chennupati Ramesh, Solga Isabella, Wischmann Patricia, Dahlmann Paul, Celik Feyza Gül, Pacht Daniela, Şahin Aslıhan, Yogathasan Vithya, Hosen Mohammad Rabiul, Gerdes Norbert, Kelm Malte, Jung Christian
Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
Department of Internal Medicine II, Heart Center Bonn, University Hospital Bonn, Bonn, Germany.
Front Cardiovasc Med. 2023 May 10;10:1099069. doi: 10.3389/fcvm.2023.1099069. eCollection 2023.
In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium.
CA was induced by repeated blood withdrawal in male C57BL/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by pharmacological inhibition of MPO.
The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice.
Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.
在急性心肌梗死和心力衰竭中，贫血与不良临床结局相关。内皮功能障碍（ED）的特征是一氧化氮（NO）介导的舒张反应减弱，而在慢性贫血（CA）中对此研究较少。我们假设CA与ED相关，是由于内皮中氧化应激增加所致。
通过反复采血诱导雄性C57BL/6J小鼠发生CA。使用超声引导的股动脉短暂缺血模型评估CA小鼠的血流介导的舒张（FMD）反应。使用组织器官浴评估CA小鼠主动脉环的血管反应性，以及与贫血患者红细胞（RBC）共同孵育的主动脉环的血管反应性。在贫血小鼠的主动脉环中，使用精氨酸酶抑制剂（Nor-NOHA）或在内皮中对精氨酸酶1进行基因敲除来评估精氨酸酶的作用。通过酶联免疫吸附测定（ELISA）检测CA小鼠血浆中的炎症变化。通过蛋白质印迹法或免疫组织化学评估内皮型一氧化氮合酶（eNOS）、诱导型一氧化氮合酶（iNOS）、髓过氧化物酶（MPO）、3-硝基酪氨酸水平和4-羟基壬烯醛（4-HNE）的表达。在贫血小鼠中，通过补充N-乙酰半胱氨酸（NAC）或通过药理学抑制MPO来评估活性氧（ROS）在ED中的作用。
FMD反应减弱，且与贫血持续时间相关。与非贫血小鼠相比，CA小鼠的主动脉环显示出NO依赖性舒张降低。与非贫血对照相比，贫血患者的RBC减弱了小鼠主动脉环中NO依赖性舒张反应。CA导致血浆血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）水平升高，且主动脉血管平滑肌细胞中iNOS表达增加。精氨酸酶抑制或精氨酸酶1缺失并未改善贫血小鼠的ED。在CA小鼠主动脉切片的内皮细胞中观察到MPO和4-HNE表达增加。补充NAC或抑制MPO可改善CA小鼠的舒张反应。
慢性贫血与进行性内皮功能障碍相关，表现为全身炎症介导的内皮激活、iNOS活性增加以及动脉壁中ROS产生。补充ROS清除剂（NAC）或抑制MPO是逆转慢性贫血中严重内皮功能障碍的潜在治疗选择。
