Mechanisms of cardiac remodeling triggered by gestational diabetes

妊娠期糖尿病引发心脏重构的机制

• 批准号: 10610933
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610933
• 关键词: Acids; Age Months; Agreement; Beta Cell; Blood; Calcineurin; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Complex; Complications of Diabetes Mellitus; Data; Deposition; Development; Female; Functional disorder; Genetic Transcription; Gestational Diabetes; Heart; Heart Diseases; Heart Hypertrophy; Histone Deacetylase; Hormones; Human; Hyperglycemia; Hypertrophy; Impairment; Incubated; Individual; Injections; Insulin; Insulin Resistance; Life; Measurement; Mediating; Mediator; 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; Poloxamer 188; Postpartum Period; Prediabetes syndrome; Pregnancy; Pregnancy Complications; Property; Prospective Studies; Rat Transgene; Rattus; Recombinants; Reporting; Risk; Risk Reduction; Role; Signal Transduction; Structure; Structure of beta Cell of islet; Testing; Woman; Work; 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; pharmacologic; population based; pregnant; programs; pup

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 妊娠糖尿病（GDM）增加了母亲患心血管疾病的风险 和后代。最近的一项大型基于人群的前瞻性研究（CARDIA）发现GDM是独立的 与心脏肥大和心脏功能受损相关。同意这一发现，我们的 初步数据显示心脏肥大和Ca2+依赖性转录信号的激活两个 雌性大鼠的GDM复杂怀孕几个月后。尽管通常认为高血糖 关键调解人，大量研究报告说，GDM即使有负面影响，即使 母亲的血糖控制良好。因此，其他机制促进了代谢和心血管 GDM中的功能障碍。我们以前证明了淀粉素的重要作用，淀粉素是一种胰腺激素 淀粉样蛋白生成特性，其分泌与心脏的分泌与胰岛素平行增加 2型糖尿病引起的重塑和功能障碍。此外，我们发现淀粉蛋白会激活Ca2+ - 心肌细胞中的依赖性转录信号传导。我们的初步研究显示 雌性大鼠的血液及其后代。基于这些发现，我们假设GDM 通过激活Ca2+依赖性，促进母体和后代心脏的病理重塑 由全身性氨基蛋白异神经素触发的肥大信号传导。为了检验这一总体假设，我们 i）确定GDM诱导的心脏病理重塑的基础的分子机制， ii）探测GDM中的氨基蛋白 - 肌细胞相互作用，iii）评估高氨基血症对 在没有与GDM相关的其他代谢改变的情况下，怀孕引起的心脏重塑。 实验将结合心脏结构和功能和药理治疗的体内评估 在雌性心脏和孤立的心肌细胞中进行测量，雌性大鼠正常和GDM- 复杂的怀孕及其后代以及注射的孕妇氨基蛋白 - 雌性 重组淀粉素。因此，该项目将为复杂机制提供独特的见解 GDM程序在母亲和后代进行心脏改造。这项研究可能是通过断言范式转移的 作为这种病理学的关键参与者，氨基蛋白Dyshomeostasis将有助于设计新的治疗策略 减少GDM母亲及其后代母亲的心脏病产后风险。