Pathogenesis of Cardiopulmonary Fibrosis Associated with Heart Failure in the Elderly

老年人心肺纤维化伴心力衰竭的发病机制

• 批准号: 10319601
• 负责人: Krishna C Penumatsa
• 金额: $ 70.43万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319601
• 关键词: Activity Cycles; Aging; Apoptosis; Attenuated; Biochemical; Biological; Biological Assay; Cardiac; Cardiopulmonary; Cardiovascular system; Cell Culture Techniques; Cell Cycle; Cells; Cellular Stress; Chronic; Cicatrix; Clinical; Collagen; Data; Deposition; Development; Diagnostic; Disease; Disease remission; EFRAC; Echocardiography; Effectiveness; Elderly; Enzymes; Event; Extracellular Matrix Proteins; Failure; Fibroblasts; Fibronectins; Fibrosis; Free Radical Formation; Functional disorder; Genus Hippocampus; Glycolysis; Goals; Heart; Heart failure; Human; Hypertrophy; Imaging Techniques; In Vitro; Inflammation; Intervention; Lead; Left; Left Ventricular Dysfunction; Left ventricular structure; Lung; Magnetic Resonance Imaging; Measurement; Mechanics; Mediating; Mediator of activation protein; Metabolism; Modeling; Molecular; Monitor; Motion; Mouse Strains; Mus; Muscle Cells; Outcome; Oxides; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiologic intraventricular pressure; Physiological; Population Attributable Risks; Positron-Emission Tomography; Protein-Lysine 6-Oxidase; Proteins; Publishing; Pulmonary Fibrosis; Pulmonary Hypertension; Reactive Oxygen Species; Regulation; Resistance; Respiratory Failure; Role; Serum; Signal Pathway; Signal Transduction; Stress; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Transcriptional Activation; Validation; Ventricular; Wild Type Mouse; Workload; age related; aged; aorta constriction; arterial stiffness; beta-Galactosidase; blood pressure elevation; constriction; coronary fibrosis; crosslink; effective therapy; fibrogenesis; fibrotic lung; free radical oxygen; hemodynamics; imaging study; in vivo; in vivo imaging; inhibitor; insight; mechanotransduction; middle age; monolayer; mouse model; novel; novel strategies; novel therapeutic intervention; oxidation; preservation; pressure; protein crosslink; protein metabolism; resistant strain; response; right ventricular failure; senescence; small molecule; small molecule inhibitor; transglutaminase 2

Project Summary/Abstract Aging-related adverse remodeling in cardiac and pulmonary tissues is increasingly recognized in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF is associated with the development of fibrosis and decreased compliance (increased stiffness) of these vital structures. In turn, this structural rigidity results in increased work load and eventual HF with poor clinical outcomes. Little is known about the basic mechanism by which this tissue stiffness occurs. We have found evidence for elevation of expression and activity of tissue transglutaminase (TG2) in age-dependent pathologies including senescence and chronic cardiac pressure overload, occurring with enhanced glycolytic metabolism. Since TG2 is known to participate in protein cross-linking and stimulation of fibrogenesis, we hypothesize that this aging-mediated enhancement of TG2 through glycolytic stress sets in motion a variety of biologic events, including fibroblast activation and extracellular matrix protein collagen deposition and cross-linking that lead to development of tissue stiffness in experimental HFpEF. We wish to explore this novel hypothesis with the idea that intervention of TG2 activity may provide a new therapeutic approach for age-related HFpEF. In Specific Aim 1, we will utilize senescent and control fibroblasts in vitro to directly explore the influence of aging-related biologic pathways on mechanistic relationships between glycolysis, TG2, lysyl oxidase (LOX), matrix protein alteration and cell signaling and physiologic function. Expected outcome: These in vitro studies will advance our understanding about upstream aging-related mechanisms that mediate TG2 induction and associated downstream signaling pathways. In Specific Aim 2, we will use wild-type mice and a senescent-accelerated mouse (SAM) model including prone (SAMP8) and resistant (SAMR1) strains with or without pressure-overload of the cardiac left ventricle (constriction of the aorta) to assess aging-related in vivo molecular and physiologic responses of cardiac and pulmonary tissue remodeling, fibrosis and stiffness. Additionally, we will use these senescent mouse models to assess the influence of ERW1041E, a TG2 inhibitor, on these pathophysiological responses to test validation of TG2 as a significant mediator of aging-dependent tissue fibrosis and HFpEF. We will determine the extent of TG2-mediated collagen accumulation and LOX-mediated collagen oxidation in cardiac and pulmonary tissues in these mice with use of novel in vivo imaging techniques and further relate them to fibrogenic progression and remission. Further, TG2-mediated matrix protein crosslinking will be assessed using a non-invasive bioassay. Expected outcome: We hope that these studies will provide new insights into mechanisms by which tissue fibrosis and stiffness occur in aging hearts and lungs. Significance: The results of our studies may lead to similar techniques in humans to assess the presence of early stages of aging- associated HFpEF and effectiveness of related therapy directed toward inhibition of tissue fibrosis.

项目总结/摘要 随着年龄的增长，越来越多的人认识到心脏和肺组织中与年龄相关的不良重塑， 射血分数正常的心力衰竭（HFpEF）。HFpEF与纤维化的发展相关 以及这些重要结构的顺应性降低（刚度增加）。反过来，这种结构刚性导致 工作量增加，最终出现心力衰竭，临床结局不佳。我们对基本的 这种组织硬度发生的机制。我们已经发现了提高表达的证据， 组织转氨酶（TG 2）在包括衰老和慢性衰老在内的年龄依赖性病理学中的活性 心脏压力超负荷，伴随糖酵解代谢增强而发生。由于已知TG 2参与了 在蛋白质交联和纤维化刺激中，我们假设这种衰老介导的增强 TG 2通过糖酵解应激的释放启动了多种生物学事件，包括成纤维细胞活化， 细胞外基质蛋白胶原沉积和交联，导致组织僵硬的发展， 实验性HFpEF。我们希望探索这一新的假设，认为TG 2活性的干预 可能为年龄相关性HFpEF提供新的治疗途径。在具体目标1中，我们将利用衰老 并在体外控制成纤维细胞，以直接探索衰老相关的生物学途径对 糖酵解、TG 2、赖氨酰氧化酶（LOX）、基质蛋白改变和细胞凋亡之间的机制关系 信号和生理功能。预期结果：这些体外研究将促进我们的理解 关于上游衰老相关的机制，介导TG 2诱导和相关的下游信号传导 途径。在具体目标2中，我们将使用野生型小鼠和衰老加速小鼠（SAM）模型 包括易感（SAMP 8）和耐药（SAMR 1）菌株，伴或不伴左心室压力超负荷 心室（主动脉收缩），以评估老化相关的体内分子和生理反应， 心脏和肺组织重塑、纤维化和僵硬。此外，我们将使用这些衰老的 小鼠模型，以评估ERW 1041 E（一种TG 2抑制剂）对这些病理生理学反应的影响 测试TG 2作为老化依赖性组织纤维化和HFpEF的重要介质的有效性。我们将 确定TG 2介导的胶原积累和LOX介导的胶原氧化在心脏中的程度， 和肺组织，并进一步将它们与 纤维化进展和缓解。此外，将评估TG 2介导的基质蛋白交联 使用非侵入性生物测定法。预期成果：我们希望这些研究将提供新的见解， 组织纤维化和僵硬在老化的心脏和肺中发生的机制。意义：结果 我们的研究可能会导致类似的技术在人类中评估老化的早期阶段的存在- 相关HFpEF和针对组织纤维化抑制的相关治疗的有效性。