A novel mechanism by which smooth muscle BMAL1 regulates IL-6 and sexual dimorphism of abdominal aortic aneurysm

平滑肌BMAL1调节IL-6和腹主动脉瘤性别二态性的新机制

基本信息

批准号：
9980987
负责人：
MING C GONG
金额：
$ 62.68万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980987
关键词：
ARNTL gene Abdominal Aortic Aneurysm Accounting Acetates Affect Age Agonist Aldosterone American Angiotensin II Animal Model Aorta Cardiovascular Diseases Cessation of life Country Data Deoxycorticosterone Disease Dissection Estrogens Female Genes Genetic Transcription Goals Gonadal Steroid Hormones Heart failure Human Hypertension Inflammatory Interleukin 6 Receptor Interleukin-6 Left Ventricular Hypertrophy Link Literature Mediating Mineralocorticoid Receptor Mus Myocardial Infarction Operative Surgical Procedures Pharmaceutical Preparations Pharmacotherapy Plasma Play Prevalence Reporting Rheumatoid Arthritis Role Rupture Serum Sex Differences Signal Transduction Smooth Muscle Sodium Chloride Stroke Testing Testosterone Therapeutic Transcriptional Regulation United States Up-Regulation Variant Vascular Diseases Woman base circadian circadian pacemaker cytokine effective therapy genome wide association study insight male men mortality neutralizing antibody new therapeutic target novel novel therapeutics pre-clinical salt intake sexual dimorphism sham surgery small molecule inhibitor

项目摘要

PROJECT SUMMARY Abdominal aortic aneurysm (AAA) is a vascular disease affecting millions of Americans that accounts for 15,000 deaths per year in the United States. Currently, open or endovascular surgery is the only therapeutic option for AAA, as no drug has been approved for treatment of this devastating disease, highlighting an urgent need for new mechanistic understandings of AAA. We recently reported that administration of mineralocorticoid receptor (MR) agonists, Aldo or deoxycorticosterone acetate (DOCA) plus salt, but not Aldo, DOCA or salt alone, to 10-month-old C57BL/6 male mice potently induces AAA, and our preliminary data demonstrated that administration of angiotensin II (Ang II) plus salt, but not Ang II alone, to 10-month-old C57BL/6 male mice also potently induces AAA. While the mechanism remains elusive, our preliminary data show that Aldo- or Ang II- salt-induced AAA occurs only or mostly in male but not in female or orchidectomized (orx) male mice. To elucidate the mechanism that underlies sexual dimorphism of AAA, we identified several genes that were selectively upregulated by Aldo-salt in aorta in male but not in female or orx male mice. Among these genes, circadian clock BMAL1 and inflammatory cytokine interleukin 6 (IL-6) are particularly promising as BMAL1 has not been previously implicated in AAA despite wide recognition that aortic dissection and aneurysmal rupture are characterized by circadian variation, and as IL-6 has been associated with human AAA by recent large genome-wide association studies (GWAS). Our preliminary data show that selective deletion of BMAL1 from smooth muscle (SM) completely abolished DOCA-salt-induced AAA and IL-6 upregulation. In addition, we found that treatment of mice with a novel small molecule inhibitor targeting the IL-6 signaling significantly diminished Aldo-salt-induced AAA. Based on these provocative preliminary data and the literature that testosterone (T) promotes AAA, whereas estrogen (E2) protects against AAA, we hypothesize that T and E2 critically regulate sexual dimorphism in Aldo- or Ang II-salt-induced AAA via SM-BMAL1 and IL-6 signaling, and further, that targeting IL-6 signaling represents a novel therapeutic strategy against AAA. Two specific aims test this central hypothesis: Aim1. To determine whether sex hormone is crucial for Aldo- or Ang II-salt to activate BMAL1 in aorta and thereby result in sexual dimorphism in Aldo- or Ang II-salt- induced AAA. Aim2. To define the mechanism by which IL-6 is transcriptionally regulated by SM-BMAL1 and to target IL-6 signaling as a novel therapeutic strategy against Aldo- or Ang II-salt-induced AAA. To achieve these aims, we will administer Aldo- or AngII-salt and/or T or E2 to 10-month-old normal or castrated C57BL/6 male or female mice, SM-BMAL1-KO, IL-6R-KO, and wild-type control mice to induce SM-BMAL1 and IL-6 signaling and AAA. The proposed studies will shed new mechanistic insight into a novel role of BMAL1 and IL-6 signaling in sexual dimorphism of AAA. Moreover, the results will provide preclinical evidence that targeting IL- 6 signaling represents a novel therapeutic strategy against AAA.

项目概要腹主动脉瘤 (AAA) 是一种影响数百万美国人的血管疾病，导致美国每年有 15,000 人死亡。目前，开放手术或血管内手术是唯一的治疗方法 AAA 的选择，因为目前还没有药物被批准用于治疗这种毁灭性的疾病，这凸显了迫切需要解决的问题需要对 AAA 有新的机制理解。我们最近报道了盐皮质激素的给药受体 (MR) 激动剂、Aldo 或醋酸脱氧皮质酮 (DOCA) 加盐，但不是 Aldo、DOCA 或盐单独使用，对 10 个月大的 C57BL/6 雄性小鼠可有效诱导 AAA，我们的初步数据表明还给 10 个月大的 C57BL/6 雄性小鼠施用血管紧张素 II (Ang II) 加盐，但不是单独使用 Ang II 有效诱导 AAA。虽然该机制仍然难以捉摸，但我们的初步数据表明 Aldo- 或 Ang II- 盐诱导的 AAA 仅或大部分发生在雄性小鼠中，但不会发生在雌性或睾丸切除 (orx) 雄性小鼠中。到为了阐明 AAA 性二态性的机制，我们鉴定了几个基因在雄性小鼠的主动脉中，醛糖盐选择性上调，但在雌性或 orx 雄性小鼠中则没有。在这些基因中，生物钟 BMAL1 和炎症细胞因子白细胞介素 6 (IL-6) 特别有前途，因为 BMAL1 尽管人们广泛认识到主动脉夹层和动脉瘤破裂，但以前并未涉及 AAA 其特点是昼夜节律变化，并且最近大量研究表明 IL-6 与人类 AAA 相关。全基因组关联研究（GWAS）。我们的初步数据表明，从平滑肌 (SM) 完全消除了 DOCA 盐诱导的 AAA 和 IL-6 上调。此外，我们发现用一种针对 IL-6 信号传导的新型小分子抑制剂治疗小鼠显着减少醛糖盐诱导的 AAA。基于这些具有争议性的初步数据和文献睾酮 (T) 促进 AAA，而雌激素 (E2) 预防 AAA，我们假设 T 和 E2 通过 SM-BMAL1 和 IL-6 关键调节 Aldo 或 Ang II 盐诱导的 AAA 中的性别二态性信号传导，而且进一步，靶向 IL-6 信号传导代表了一种新的治疗策略 AAA。两个具体目标检验了这个中心假设：目标1。确定性激素是否至关重要 Aldo-或Ang II-salt激活主动脉中的BMAL1，从而导致Aldo-或Ang II-salt-的性别二态性- 诱发 AAA。目标2。定义 SM-BMAL1 转录调节 IL-6 的机制并靶向 IL-6 信号传导作为针对 Aldo 或 Ang II 盐诱导的 AAA 的新型治疗策略。为了实现这些为了实现这一目标，我们将给 10 个月大的正常或阉割的 C57BL/6 雄性施用 Aldo-或 AngII-盐和/或 T 或 E2 或雌性小鼠、SM-BMAL1-KO、IL-6R-KO 和野生型对照小鼠诱导 SM-BMAL1 和 IL-6 信号传导和 AAA。拟议的研究将为 BMAL1 和 IL-6 的新作用提供新的机制见解 AAA 性二态性中的信号传导。此外，结果将提供临床前证据，表明靶向IL- 6 信号传导代表了一种针对 AAA 的新型治疗策略。