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

• 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
• 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

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，这是导致死亡原因 全球。因此，所有心血管死亡中有80％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与衰老相关的分泌表型（SASP）为特征，是 与年龄相关的心血管功能障碍的主要贡献者。但是，内皮的机制 细胞经历衰老仍不清楚。 我们最近做出了新颖的发现，使内皮细胞HSPA12B缺陷（EHSPA12B - / - ）显示 心脏内皮细胞衰老伴随着严重的心脏肥大，纤维化和持续性 与年龄和性别匹配的WT对照相比，炎症。我们的发现表明衰老 内皮细胞在心脏肥大和成纤维细胞激活的调节中起重要作用 该内皮细胞HSPA12B限制了内皮细胞的衰老。因此，了解 HSPA12B调节内皮细胞衰老的机制对于寻求 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如何限制内皮细胞的衰老，我们检查了HSPA12B对 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是调节的重要转录因子 与适当蛋白质折叠和细胞衰老有关的基因的表达。曼夫是进化 保守的保护剂，用于维持组织免疫和代谢稳态。 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介导的保护性 对内皮细胞衰老的影响。 为了研究内皮细胞衰老如何促进心脏肥大，我们检查了心脏 线粒体葡萄糖氧化（MGO）是造成心肌能量产生的主要因素之一。 线粒体葡萄糖氧化受损会导致心脏肥大的发展，并最终 心脏衰竭。我们观察到EHSPA12B - / - 导致乙酰辅酶A降低，乳酸增加 积累。数据表明EHSPA12B - / - 会损害心脏线粒体葡萄糖氧化。我们的 观察还表明，衰老的内皮细胞通过损害诱导心脏肥大 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），将培养基作为衰老条件培养基（SCM）收集，并处理过的成年 SCM的心肌细胞。我们观察到SCM促进了葡萄糖的代谢重编程 通过增加PDK4（丙酮酸脱氢酶激酶4）和 降低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 失活。 TFAM是通过调节线粒体生物发生的核心线粒体转录因子 mtDNA复制和转录。 该应用是破译HSPA12B在与年龄相关的内皮细胞衰老中的作用以及如何 内皮细胞衰老会导致心脏肥大和功能障碍。根据我们的小说发现，我们 假设：i）HSPA12B限制内皮细胞衰老是通过ATF6/MANF的激活介导的 信号和那个； ii）内皮细胞衰老通过 心肌细胞中线粒体葡萄糖氧化受损。为了批判性评估这一假设，我们提出了 以下特定目标。目标1。定义HSPA12B调节ATF6转录的机制 活性和限制内皮细胞衰老。目标2。研究内皮细胞衰老在 与年龄有关的心脏肥大及其潜在机制。 成功完成拟议的研究将导致大量新的数据显示新角色 HSPA12B在调节内皮细胞衰老的调节中介导的ATF6。衰老的内皮细胞 有助于与年龄相关的心脏代谢疾病和肥大。这些新发现将是 与年龄相关的心肌病的创新疗法的开发。