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.

项目摘要腹主动脉瘤（AAA）是一种血管疾病，影响了数百万美国人美国每年15,000人死亡。目前，开放或血管内手术是唯一的治疗 AAA的选择，因为没有批准药物治疗这种毁灭性疾病，因此强调了紧急需要对AAA的新机械理解。我们最近报道了矿物皮质激素的给药受体（MR）激动剂，Aldo或脱氧核心酮（DOCA）加盐，但不是Aldo，Doca或Salt 单独使用10个月大的C57BL/6雄性小鼠有效诱导AAA，我们的初步数据表明这表明血管紧张素II（ANG II）加盐，而不是单独使用ANG II，也要给10个月大的C57BL/6雄鼠有力诱导AAA。尽管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仅发生或主要发生在雄性或雌性或兰花切除（Orx）雄性小鼠中。到阐明了AAA性二态性二态性的机制，我们确定了几个基因 Aldo-Salt在主动脉中有选择地上调雄性，但在雌性或ORX雄性小鼠中没有选择性上调。在这些基因中，昼夜节律BMAL1和炎性细胞因子白介素6（IL-6）特别有前途，因为BMAL1已有尽管广泛认识到主动脉夹层和动脉瘤破裂，但以前没有与AAA有关具有昼夜节律的特征，并且由于IL-6与人类AAA有关全基因组关联研究（GWAS）。我们的初步数据表明，从中选择性删除BMAL1 平滑肌（SM）完全废除了DOCA盐诱导的AAA和IL-6上调。另外，我们发现用靶向IL-6信号的新型小分子抑制剂对小鼠进行处理 Aldo-Salt诱导的AAA减少。基于这些挑衅性的初步数据和文献睾丸激素（t）促进了AAA，而雌激素（E2）可以预防AAA，我们假设T和E2 通过SM-BMAL1和IL-6，严重调节Aldo或Ang II-盐诱导的AAA的性二态性信号传导，进一步的，靶向IL-6信号传导代表了一种针对的新型治疗策略 AAA。两个具体的目的测试了这一中心假设：AIM1。确定性激素是否对 Aldo-或Ang II盐以激活主动脉中的BMAL1，从而导致Aldo-或Ang II-Salt-的性二态性诱导的AAA。 AIM2。定义IL-6在转录下由SM-BMAL1和TO的机制目标IL-6信号传导是针对Aldo或ANG II-盐诱导的AAA的新型治疗策略。实现这些目的，我们将管理Aldo-或Angii-Salt和/或T或E2至10个月大的正常或cast割C57BL/6男性或雌性小鼠，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。拟议的研究将对BMAL1和IL-6的新作用进行新的机械洞察力。 AAA性二态性的信号传导。此外，结果将提供临床前证据，以靶向IL- 6信号传导代表了针对AAA的新型治疗策略。