Role of endothelial cell senescence in age-related cardiomyopathy

内皮细胞衰老在年龄相关性心肌病中的作用

基本信息

批准号：
10726050
负责人：
Xiaohui Wang
金额：
$ 22.5万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726050
关键词：
ATF6 gene Acetyl Coenzyme A Address Adult Age Aging Astrocytes Biogenesis Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cause of Death Cell Aging Cell Cycle Arrest Cell Senescence Induction Cessation of life Conditioned Culture Media Data Development Disease Endothelial Cells Endothelium Enzymes Etoposide Exhibits Fibroblasts Fibrosis Functional disorder Gender Gene Expression Genes Genetic Transcription Glucose Glycolysis Heart Hypertrophy Heart failure Homeostasis Hypertrophy Immune Impairment Inflammation Innovative Therapy Maintenance Mediating Metabolic Metabolic Diseases Mitochondria Mitochondrial DNA Mus Myocardial Myocardial dysfunction Patients Phenotype Phosphorylation Play Production Pyruvate Regulation Role Signal Transduction Tissues Transcriptional Activation age related blood glucose regulation cardiovascular risk factor factor A human old age (65+)mtTF1 transcription factor neurotrophic factor novel oxidation prevent protective effect protein folding pyruvate dehydrogenase kinase 4 senescence transcription factor

项目摘要

Abstract Age is a major risk factor for cardiovascular associated diseases which are leading causes of death globally. Accordingly, 80% of all cardiovascular deaths occurred in patients aged 65 and over. Endothelial cell senescence, characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP), is a major contributor to age related cardiovascular dysfunction. However, the mechanism by which endothelial cells are subjected to senescence is still unclear. We have recently made novel findings that endothelial cell HSPA12B deficient (eHSPA12B-/-) mice exhibit cardiac endothelial cell senescence accompanied by severe cardiac hypertrophy, fibrosis, and persistent inflammation when compared with age- and gender-matched WT controls. Our findings suggest that senescent endothelial cells play an important role in the regulation of cardiac hypertrophy and fibroblast activation and that endothelial cell HSPA12B limits senescence of endothelial cells. Therefore, understanding the mechanisms by which HSPA12B regulates endothelial cell senescence would be important for seeking an approach to prevent or reverse senescent endothelial cells, thus reducing age-related cardiovascular disease. To elucidate how HSPA12B limits senescence of endothelial cells, we examined the effect of HSPA12B on ATF6 (Activating transcription factor 6) transcriptional activity and its target gene MANF (Mesencephalic Astrocyte Derived Neurotrophic Factor) expression. ATF6 is an important transcriptional factor that regulates the expression of genes involved in proper protein folding and cellular senescence. MANF is an evolutionarily conserved protective modulator for the maintenance of tissue immune and metabolic homeostasis. Interestingly, we observed that HSPA12B is critical for sustaining ATF6 transcriptional activity and MANF expression. The data suggest that ATF6 and MANF may be involved in the HSPA12B mediated protective effect on endothelial cell senescence. To investigate how endothelial cell senescence contributes to cardiac hypertrophy, we examined cardiac mitochondrial glucose oxidation (MGO) which is one of the major contributors to myocardial energy production. Compromised mitochondrial glucose oxidation leads to the development of cardiac hypertrophy and eventually heart failure. We observed that eHSPA12B-/- resulted in decreased Acetyl-CoA and increased lactate accumulation. The data indicate that eHSPA12B-/- impairs cardiac mitochondrial glucose oxidation. Our observation also suggests that senescent endothelial cells induce cardiac hypertrophy via impairment of cardiac myocyte MGO (mitochondrial glucose oxidation). To address how endothelial cell senescence impairs cardiac MGO, we induced endothelial cell senescence by ETO (etoposide), collected the medium as the senescent conditioned medium (SCM), and treated adult cardiac myocytes with the SCM. We observed that SCM promotes metabolic reprogramming from glucose oxidation to glycolysis in adult cardiac myocytes by increasing PDK4 (Pyruvate Dehydrogenase Kinase 4) and decreasing TFAM (Mitochondrial transcription factor A). PDK4 is a key enzyme in the regulation of glucose oxidation by inhibiting the conversion of pyruvate into Acetyl-CoA via promoting PDH phosphorylation and inactivation. TFAM is a core mitochondrial transcription factor for mitochondrial biogenesis by regulating mtDNA replication and transcription. This application is to decipher the role of HSPA12B in age-related endothelial cell senescence and how endothelial cell senescence results in cardiac hypertrophy and dysfunction. Based on our novel findings, we hypothesize that: i) HSPA12B limits endothelial cell senescence is mediated by activation of ATF6/MANF signaling and that; ii) endothelial cell senescence contributes to cardiac hypertrophy and dysfunction via impaired mitochondrial glucose oxidation in cardiomyocytes. To critically evaluate this hypothesis, we propose the following specific aims. Aim 1. Define the mechanisms by which HSPA12B regulates ATF6 transcriptional activity and limits endothelial cell senescence. Aim 2. Investigate the role of endothelial cell senescence in age-related cardiac hypertrophy and its underlying mechanisms. Successful completion of the proposed studies will result in a wealth of novel data showing the novel role of HSPA12B mediated ATF6 in the regulation of endothelial cell senescence. The senescent endothelial cells contribute to age-related cardiac metabolic disorders and hypertrophy. These new findings will be the basis for the development of innovative therapies for age-related cardiomyopathy.

抽象的年龄是心血管相关疾病的主要危险因素，而心血管相关疾病是导致死亡的主要原因全球。因此，80% 的心血管死亡发生在 65 岁及以上的患者中。内皮细胞衰老以细胞周期停滞和衰老相关分泌表型（SASP）为特征，是一种与年龄相关的心血管功能障碍的主要原因。然而，内皮细胞的机制细胞是否会衰老目前尚不清楚。我们最近有了新的发现，内皮细胞 HSPA12B 缺陷 (eHSPA12B-/-) 小鼠表现出心脏内皮细胞衰老并伴有严重的心脏肥大、纤维化和持续性与年龄和性别匹配的 WT 对照相比，炎症发生率更高。我们的研究结果表明，衰老内皮细胞在心脏肥大和成纤维细胞活化的调节中发挥重要作用内皮细胞 HSPA12B 限制内皮细胞的衰老。因此，了解 HSPA12B 调节内皮细胞衰老的机制对于寻找预防或逆转衰老内皮细胞的方法，从而减少与年龄相关的心血管疾病。为了阐明 HSPA12B 如何限制内皮细胞衰老，我们研究了 HSPA12B 对内皮细胞衰老的影响。 ATF6（激活转录因子6）转录活性及其靶基因MANF（中脑星形胶质细胞衍生的神经营养因子）表达。 ATF6是重要的转录因子，调节参与正确蛋白质折叠和细胞衰老的基因的表达。 MANF 是一个进化的用于维持组织免疫和代谢稳态的保守保护调节剂。有趣的是，我们观察到 HSPA12B 对于维持 ATF6 转录活性和 MANF 至关重要表达。数据表明 ATF6 和 MANF 可能参与 HSPA12B 介导的保护作用对内皮细胞衰老的影响。为了研究内皮细胞衰老如何导致心脏肥大，我们检查了心脏线粒体葡萄糖氧化（MGO）是心肌能量产生的主要贡献者之一。线粒体葡萄糖氧化受损导致心脏肥大，最终心脏衰竭。我们观察到 eHSPA12B-/- 导致乙酰辅酶 A 减少和乳酸增加积累。数据表明 eHSPA12B-/- 损害心脏线粒体葡萄糖氧化。我们的观察结果还表明，衰老的内皮细胞通过损伤心脏功能而诱发心脏肥大。心肌细胞 MGO（线粒体葡萄糖氧化）。为了解决内皮细胞衰老如何损害心脏 MGO，我们诱导内皮细胞衰老通过ETO（依托泊苷），收集培养基作为衰老条件培养基（SCM），并处理成体心肌细胞与 SCM。我们观察到 SCM 促进葡萄糖代谢重编程通过增加 PDK4（丙酮酸脱氢酶激酶 4）和减少 TFAM（线粒体转录因子 A）。 PDK4是调节葡萄糖的关键酶通过促进 PDH 磷酸化和抑制丙酮酸转化为乙酰辅酶 A 来抑制氧化失活。 TFAM 是线粒体生物合成的核心转录因子，通过调节线粒体DNA复制和转录。本应用旨在破译 HSPA12B 在年龄相关内皮细胞衰老中的作用以及如何发挥作用内皮细胞衰老导致心脏肥大和功能障碍。根据我们的新发现，我们假设： i) HSPA12B 限制内皮细胞衰老是由 ATF6/MANF 激活介导的信令等； ii) 内皮细胞衰老通过以下途径导致心脏肥大和功能障碍心肌细胞中线粒体葡萄糖氧化受损。为了批判性地评估这个假设，我们建议具体目标如下。目标 1. 明确 HSPA12B 调节 ATF6 转录的机制活性并限制内皮细胞衰老。目标 2. 研究内皮细胞衰老在年龄相关的心脏肥大及其潜在机制。成功完成拟议的研究将产生大量新数据，显示新的作用 HSPA12B 介导的 ATF6 在内皮细胞衰老调节中的作用。衰老的内皮细胞导致与年龄相关的心脏代谢紊乱和肥厚。这些新发现将成为以下研究的基础与年龄相关的心肌病的创新疗法的开发。