Targeting mitochondria-derived reactive oxygen species as a therapy for combined pre- and post-capillary pulmonary hypertension

靶向线粒体衍生的活性氧作为治疗毛细血管前和后联合肺动脉高压的方法

• 批准号: 10535666
• 负责人: Georgios Triantafyllou
• 金额: $ 8.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535666
• 关键词: Acute; Anatomy; Animal Experiments; Animals; Antioxidants; Apoptosis; Blood Vessels; Blood capillaries; Calcium; Cardiac; Cell Culture Techniques; Cell Proliferation; Clinical Trials Design; Cyclic GMP; Down-Regulation; EFRAC; Echocardiography; Educational workshop; Endothelium; Enzymes; Evaluation; Exercise; Exercise Tolerance; Failure; Future; GUCY1B3 gene; Generations; Grant; Guanosine Monophosphate; Health; Heart failure; Hospitalization; Human; Hypertrophy; Impairment; Institute of Medicine (U.S.); Knowledge; Leadership; Learning; Left; Left Ventricular Function; Lung; Measures; Mentors; Metabolic syndrome; Methods; MicroRNAs; Mitochondria; Modeling; Molecular Biology Techniques; National Heart, Lung, and Blood Institute; Nuclear; Obesity; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathogenesis; Patients; Periodicity; Persons; Pharmaceutical Preparations; Physicians; Positioning Attribute; Pre-Clinical Model; Prognosis; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary Wedge Pressure; Pulmonary artery structure; Rattus; Reactive Oxygen Species; Research Personnel; Research Priority; Rest; Risk; SU 5416; Scientist; Signal Transduction; Signs and Symptoms; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Syndrome; Technical Expertise; Testing; Thinness; Training; Translations; United States National Institutes of Health; Universities; Vascular remodeling; Vasodilation; Wedge Pressures; arterial stiffness; career development; effective therapy; exercise intensity; heart function; hemodynamics; human disease; human model; hypertension control; improved; in vivo; mortality; nuclear factor Y; preservation; pressure; pulmonary arterial pressure; pulmonary vascular disorder; pulmonary vasoconstriction; readmission rates; skills; therapeutic target; transcription factor; ultrasound

PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is common in left heart failure and is present in both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction (HFpEF). HFpEF afflicts approximately 32 million people globally with five year mortality and readmission rates estimated at 75.7% and 84%, respectively. PH is present in 83% of patients with HFpEF (PH-HFpEF) and portends worse prognosis. PH-HFpEF is classified in isolated post-capillary pulmonary hypertension (IpcPH) and combined pre- and post-capillary pulmonary hypertension (CpcPH). Both forms are characterized by increased pulmonary artery mean and wedge pressures, but the distinctive hallmark between the two is the presence of elevated pulmonary vascular resistance in CpcPH, due to intrinsic pulmonary vasoconstriction and vascular remodeling. CpcPH confers increased mortality and hospitalization risk compared to IpcPH. There are no proven or approved treatments for PH-HFpEF and finding a treatment has been identified as an unmet need by the NHLBI. We published that mitochondria-derived reactive oxygen species (mROS) produced by metabolic syndrome and maximal intensity exercise in CpcPH decrease the expression of the nitric oxide receptor soluble guanylate cyclase subunit b1 (sGCb1) by downregulating the expression of the sGC transcription factor Nuclear Factor Y subunit alpha (NFYα). Downregulation of sGC leads to lower concentration of the vasodilatory cyclic guanosine monophosphate (cGMP) impairing pulmonary artery vasodilation. Additionally, mROS decrease pulmonary artery smooth muscle cell (PASMC) apoptosis and increase vascular tone by increasing intracellular calcium in PASMCs. The long-term objective of this proposal is to test mitoquinol, a mitochondria-targeted antioxidant as treatment for CpcPH. Mitoquinol was chosen because it is mitochondria specific, and safe for use in humans, allowing for translation of our findings. We hypothesize that mitoquinol treatment of PASMCs from rats with CpcPH will decrease mROS formation and rescue NFYα-sGC expression, increase apoptosis and decrease proliferation of PASMCs (Aim 1); and mitoquinol treatment of a rat CpcPH model will decrease pulmonary artery pressures by decreasing mROS in the smooth muscle cell layer of the pulmonary artery (Aim 2). Our lab has established cell culture models to induce mROS and measure NFYα-sGC expression, cellular apoptosis and proliferation. In addition we developed a CpcPH rat model and methods to measure pulmonary artery hemodynamics at rest and during exercise. Cardiac evaluation will be supplemented using ultrasound. Completion of the proposed aims will identify mROS as a therapeutic target for CpcPH and pave the way for clinical trial design since mitoquinol has been found safe in humans. These outcomes, in addition to career development, mentored training, and didactic workshops, will provide the primary investigator with the background knowledge, technical expertise, and leadership skills necessary to proceed towards scientific independence as a physician-scientist. The objectives of this training grant will be performed at the Vascular Medicine Institute of the University of Pittsburgh.

项目摘要/摘要 肺动脉高压（pH）在左心衰竭中很常见，并且在降低的心力衰竭中存在 射血分数和心力衰竭，并保留了射血分数（HFPEF）。 HFPEF大约32 全球有5年死亡率和再入院率分别为75.7％和84％。 在83％的HFPEF（pH-HFPEF）患者中，pH值呈现，预后预后较差。 pH-HFPEF被分类 在孤立的毛细血管后肺动脉高压（IPCPH）中，并结合了乳房前后肺 高血压（CPCPH）。两种形式的特征都有增加的肺动脉平均值和楔形压力， 但是两者之间的独特标志是CPCPH中存在较高的肺血管耐药性， 由于固有的肺血管收缩和血管重塑。 CPCPH承认死亡率增加和 与IPCPH相比，住院风险。 pH-HFPEF没有经过验证或批准的治疗方法 NHLBI已将治疗方法确定为未满足的需求。我们发表了线粒体衍生的反应性 由代谢综合征和CPCPH中最大强度运动产生的氧（MRO）降低 一氧化氮受体固体鸟烯酸环酸酶亚基B1（SGCB1）的表达通过下调 SGC转录因子核因子y亚基α（NFYα）的表达。 SGC线索的下调 降低血管舒张循环鸟苷单磷酸（CGMP）损害肺动脉 血管舒张。此外，MROS减少肺动脉平滑肌细胞（PASMC）凋亡和 通过增加PASMC的细胞内钙来增加血管张力。该提议的长期目标 是测试线粒体靶向抗氧化剂作为CPCPH的治疗方法。选择了mitquinol 因为它是特定于线粒体的，并且可以安全地用于人类，因此可以翻译我们的发现。我们 假设MITOQUINOL治疗来自CPCPH大鼠的PASMC将降低MROS的形成和 拯救NFYα-SGC表达，增加凋亡并减少PASMC的增殖（AIM 1）；和 MITOQUNOL治疗大鼠CPCPH模型将通过降低MROS中的MROS减轻肺动脉压力 肺动脉的平滑肌细胞层（AIM 2）。我们的实验室已经建立了细胞培养模型 诱导MROS并测量NFYα-SGC表达，细胞凋亡和增殖。另外，我们开发了 CPCPH大鼠模型和方法在休息和运动过程中测量肺动脉血流动力学。 心脏评估将使用超声进行补充。拟议的目标的完成将确定MRO 作为CPCPH的治疗目标，并为临床试验设计铺平了道路，因为Mitoquinol已被发现安全 在人类中。这些成果，除了职业发展外，还进行了培训和教学研讨会，还将 向主要研究者提供背景知识，技术专长和领导能力 作为身体科学家的科学独立性，必不可少的。这项培训的目标 格兰特将在匹兹堡大学的血管医学研究所进行。