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.

项目概要/摘要 肺动脉高压（PH）在左心衰竭中很常见，并且存在于心力衰竭和心力衰竭中。 射血分数和射血分数保留的心力衰竭 (HFpEF) 影响约 32 例。 全球 10 万人的五年死亡率和再入院率估计分别为 75.7% 和 84%。 83% 的 HFpEF (PH-HFpEF) 患者存在 PH，预示着 PH-HFpEF 预后较差。 单纯性毛细血管后肺动脉高压（IpcPH）以及毛细血管前和毛细血管后合并肺动脉高压 高血压（CpcPH）的特点是肺动脉平均压和楔压增加， 但两者之间的显着特征是 CpcPH 中存在肺血管阻力升高， 由于内在的肺血管收缩和血管重塑，CpcPH 会导致死亡率增加。 与 IpcPH 相比的住院风险 目前尚无针对 PH-HFpEF 的经过验证或批准的治疗方法，并且没有发现任何发现。 我们发表了一种由线粒体衍生的反应性治疗方法，该治疗方法已被 NHLBI 确定为未满足的需求。 代谢综合征和最大强度运动导致 CpcPH 降低产生的氧簇 (mROS) 通过下调一氧化氮受体可溶性鸟苷酸环化酶亚基 b1 (sGCb1) 的表达 sGC 转录因子核因子 Y 亚基 α (NFYα) 的表达导致 sGC 下调。 降低损害肺动脉的血管舒张环磷酸鸟苷（cGMP 浓度） 此外，mROS 还可减少肺动脉平滑肌细胞 (PASMC) 细胞凋亡和血管舒张作用。 通过增加 PASMC 中的细胞内钙来增加血管张力 该提案的长期目标。 是为了测试 Mitoquinol，一种线粒体靶向抗氧化剂，被选为 CpcPH 的治疗方法。 因为它是线粒体特异性的，并且可以安全地用于人类，从而可以转化我们的发现。 米托喹诺对 CpcPH 大鼠的 PASMC 进行处理后，会减少 mROS 的形成，并且 挽救 NFYα-sGC 表达，增加 PASMC 凋亡并减少增殖（目标 1）； 米托喹诺治疗大鼠 CpcPH 模型将通过减少体内 mROS 来降低肺动脉压力 肺动脉平滑肌细胞层（目标2）。 诱导 mROS 并测量 NFYα-sGC 表达、细胞凋亡和增殖。 CpcPH 大鼠模型和测量静息和运动时肺动脉血流动力学的方法。 心脏评估将通过超声进行补充，完成拟议的目标将确定 mROS。 作为 CpcPH 的治疗靶点，并为临床试验设计铺平道路，因为米托喹诺已被发现是安全的 除了职业发展、指导培训和教学研讨会之外，这些成果还将在人类中发挥作用。 为主要研究者提供背景知识、技术专长和领导技能 作为一名医生科学家走向科学独立所必需的本次培训的目标。 拨款将在匹兹堡大学血管医学研究所进行。