The Effects of Spironolactone on Inflammation in a Rodent Model of Pulmonary Arterial Hypertension

螺内酯对肺动脉高压啮齿动物模型炎症的影响

• 批准号: 10262630
• 负责人: Jason Matthew Elinoff
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262630
• 关键词: Animal Model; Antiinflammatory Effect; Cardiac; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cessation of life; Diagnosis; Disease; ERCC3 gene; Exposure to; Goals; Heart; Heart failure; Hypoxia; In Vitro; Inflammation; Inflammatory; KDR gene; Left; Magnetic Resonance Imaging; Manuscripts; Mineralocorticoid Receptor; Modeling; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Preparation; Progressive Disease; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Reproducibility; Rodent Model; SU 5416; Side; Signal Transduction; Spironolactone; Stress; Structure; Subcutaneous Injections; Transcription Factor AP-1; VEGFA gene; Ventricular; eplerenone; heart function; improved; inhibitor/antagonist; pressure; pulmonary arterial hypertension; pulmonary artery endothelial cell

PAH encompasses a group of rare but lethal diseases characterized by progressive narrowing and occlusion of the small pulmonary arteries, stress on the right-side of the heart and eventually death from right-heart failure. New treatments are urgently needed because current therapy does not reverse this progressive disease and 50% of patients die within 7 years of their diagnosis. Inflammation has recently been recognized as an important part of the abnormal pulmonary arteries in patients with PAH, and therefore it has been hypothesized that drugs that block inflammation may have benefits in patients with PAH. Mineralocorticoid receptor (MR) antagonists improve patient outcomes in variety of cardiovascular diseases. Treatment with spironolactone or eplerenone, both MR antagonists, improves right heart function and pulmonary artery pressure in animal models of pulmonary hypertension. These effects are primarily believed to be a result of inhibiting the harmful effects of MR. While MR independent anti-inflammatory effects of spironolactone have been recognized for decades, the mechanism was poorly understood and the effects of spironolactone on inflammation in PAH have not been previously studied. Our group has uncovered an MR-independent mechanism whereby spironolactone suppresses inflammation in pulmonary artery endothelial cells in vitro. We identified XPB degradation as a shared, MR-independent mechanism by which spironolactone inhibits both NF-B and AP-1 inflammatory signaling. Unlike spironolactone, eplerenone did not cause XPB degradation and failed to suppress inflammatory signaling (Elinoff JM et al. Cardiovasc Res. 2018). This study has been completed and a manuscript describing the effects of MR antagonists on ventricular interdependence in the SU-5416/hypoxia/normoxia rat model of PAH is currently in preparation.

PAH包括一组罕见但致命的疾病，其特征是小肺动脉进行性狭窄和闭塞，心脏右侧受压，最终死于右心衰竭。迫切需要新的治疗方法，因为目前的治疗方法不能逆转这种进行性疾病，50%的患者在诊断后7年内死亡。炎症最近被认为是PAH患者肺动脉异常的重要组成部分，因此假设阻断炎症的药物可能对PAH患者有益。 盐皮质激素受体（MR）拮抗剂可改善多种心血管疾病患者的结局。在肺动脉高压动物模型中，使用螺内酯或依普利酮（均为MR拮抗剂）治疗可改善右心功能和肺动脉压。这些作用主要被认为是抑制MR的有害作用的结果。虽然几十年来已认识到螺内酯的MR非依赖性抗炎作用，但对其机制了解甚少，并且之前尚未研究过螺内酯对PAH炎症的影响。我们的小组已经发现了一个MR独立的机制，螺内酯抑制炎症在肺动脉内皮细胞在体外。我们确定XPB降解是一种共享的、MR独立的机制，螺内酯通过该机制抑制NF-B和AP-1炎症信号传导。与螺内酯不同，依普利酮不会引起XPB降解，也无法抑制炎症信号传导（Elinoff JM et al. Atriovasc Res. 2018）。 本研究已完成，目前正在编写描述MR拮抗剂对SU-5416/缺氧/常氧PAH大鼠模型中心室相互依赖性影响的手稿。