Mechanisms of cardiac remodeling triggered by gestational diabetes

妊娠期糖尿病引发心脏重构的机制

基本信息

批准号：
10421274
负责人：
Sanda Despa
金额：
$ 42.54万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421274
关键词：
Acids Age-Months Agreement Beta Cell Blood Calcineurin Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Complex Data Deposition Development Female Functional disorder Genetic Transcription Gestational Diabetes Heart Heart Diseases Heart Hypertrophy Histone Deacetylase Hormones Human Hyperglycemia Hypertrophy Impairment Individual Injections Insulin Insulin Resistance Life Measurement Mediating Mediator of activation protein Membrane Metabolic Modeling Molecular Mothers Muscle Cells Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Pancreatic Hormones Participant Pathologic Pathology Pathway interactions Pharmacological Treatment Pharmacology Poloxamer 188 Postpartum Period Prediabetes syndrome Pregnancy Property Prospective Studies Rattus Recombinants Reporting Risk Role Signal Transduction Structure Structure of beta Cell of islet Testing Transgenic Organisms Woman Work base blood treatment calmodulin-dependent protein kinase II design diabetic experimental study glycemic control heart dimension/size heart disease risk heart function in vivo insight insulin secretion islet amyloid polypeptide male neonate novel therapeutic intervention nuclear factors of activated T-cells offspring population based pregnant programs pup

项目摘要

ABSTRACT Gestational diabetes mellitus (GDM) heightens the risk of developing cardiovascular disease in both mother and offspring. A recent large population-based prospective study (CARDIA) found that GDM is independently associated with cardiac hypertrophy and impaired heart function later in life. In agreement with this finding, our preliminary data show cardiac hypertrophy and activation of Ca2+-dependent transcriptional signaling two months after a GDM-complicated pregnancy in female rats. Although hyperglycemia is generally considered the critical mediator, numerous studies reported that GDM has negative long term consequences even with good glycemic control in the mother. Thus, additional mechanisms promote metabolic and cardiovascular dysfunction in GDM. We previously demonstrated an essential role for amylin, a pancreatic hormone with amyloidogenic properties and whose secretion increases in parallel with that of insulin, in the cardiac remodeling and dysfunction induced by type-2 diabetes. Moreover, we found that amylin activates Ca2+- dependent transcriptional signaling in cardiac myocytes. Our preliminary studies show higher amylin levels in blood from female rats with GDM and their offspring. Based on these findings, we hypothesize that GDM promotes pathological remodeling of maternal and offspring heart through activation of Ca2+-dependent hypertrophy signaling that is triggered by systemic amylin dyshomeostasis. To test this overall hypothesis, we will i) determine the molecular mechanisms underlying the GDM-induced pathological remodeling of the heart, ii) probe the amylin-cardiac myocyte interaction in GDM, and iii) assess the effect of hyperamylinemia on pregnancy-induced cardiac remodeling in the absence of other metabolic alterations associated with GDM. Experiments will combine in vivo assessment of heart structure and function and pharmacological treatment with measurements in explanted hearts and isolated cardiac myocytes in female rats with normal and GDM- complicated pregnancies and their offspring as well as in pregnant amylin-KO females injected with recombinant amylin. Thus, the project will provide unique insights into the complex mechanisms through which GDM programs cardiac remodeling in mother and offspring. The study may be paradigm shifting by asserting amylin dyshomeostasis as a key player in this pathology, which will help design new therapeutic strategies for reducing the postpartum risk of heart disease in mothers with GDM and their offspring.

抽象的妊娠期糖尿病（GDM）会增加母亲患心血管疾病的风险和后代。最近一项基于人群的大型前瞻性研究 (CARDIA) 发现，GDM 与与晚年心脏肥大和心脏功能受损有关。与这一发现一致，我们的初步数据显示心脏肥大和 Ca2+ 依赖性转录信号传导两个激活雌性大鼠 GDM 并发症妊娠后几个月。尽管通常认为高血糖作为关键的中介因素，大量研究报告称，GDM 会产生负面的长期后果，即使母亲的血糖控制良好。因此，其他机制促进代谢和心血管 GDM 功能障碍。我们之前证明了胰淀素（一种胰腺激素）的重要作用淀粉样蛋白生成特性，其分泌量与胰岛素平行增加，在心脏中 2型糖尿病引起的重塑和功能障碍。此外，我们发现胰淀素激活Ca2+- 心肌细胞中依赖的转录信号传导。我们的初步研究表明，胰岛淀粉样蛋白水平较高来自患有 GDM 的雌性大鼠及其后代的血液。基于这些发现，我们假设 GDM 通过激活 Ca2+ 依赖性促进母体和子代心脏的病理性重塑由全身胰淀素稳态失调触发的肥大信号。为了检验这个总体假设，我们 i) 确定 GDM 诱导的心脏病理重塑的分子机制， ii) 探讨 GDM 中胰岛淀粉样蛋白与心肌细胞的相互作用，以及 iii) 评估高胰岛淀粉样蛋白血症对心肌细胞的影响在没有与 GDM 相关的其他代谢改变的情况下，妊娠引起的心脏重塑。实验将结合心脏结构和功能的体内评估以及药物治疗对正常和 GDM 雌性大鼠的移植心脏和分离心肌细胞进行测量复杂的妊娠及其后代以及注射胰岛淀粉样蛋白 KO 的怀孕女性重组胰淀素。因此，该项目将为复杂的机制提供独特的见解，通过这些机制 GDM 计划对母亲和后代进行心脏重塑。这项研究可能会通过断言来改变范式胰淀素稳态失调是这种病理学的关键因素，这将有助于设计新的治疗策略降低患有 GDM 的母亲及其后代患心脏病的风险。