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: 10152668
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152668
• 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

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.

摘要 妊娠期糖尿病（GDM）增加了母亲双方患心血管疾病的风险 和后代。最近的一项大型人群前瞻性研究（CARDIA）发现，GDM是独立的 与心脏肥大和心脏功能受损有关。根据这一发现，我们 初步数据显示，心肌肥大和激活钙依赖的转录信号两个 在雌性大鼠GDM并发妊娠后数月。虽然高血糖通常被认为是 关键的调解人，许多研究报告说，GDM有负面的长期后果，即使与 母亲血糖控制良好因此，额外的机制促进代谢和心血管 GDM的功能障碍。我们以前证明了胰淀素的重要作用，胰淀素是一种胰腺激素， 淀粉样蛋白的性质，其分泌增加与胰岛素平行，在心脏 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Ca 2 +- 依赖于心肌细胞中的转录信号。我们的初步研究表明， GDM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Ca 2+依赖性促进母体和子代心脏的病理性重塑 肥大信号传导由系统性胰淀素平衡失调触发。为了验证这个假设，我们 i）确定GDM诱导的心脏病理性重塑的分子机制， ii）探测GDM中的淀粉样蛋白-心肌细胞相互作用，和iii）评估高淀粉样蛋白血症对GDM的影响。 妊娠诱导的心脏重塑，而不存在与GDM相关的其他代谢改变。 实验将联合收割机结合心脏结构和功能的体内评估和药物治疗 在正常和GDM雌性大鼠的离体心脏和离体心肌细胞中进行测量， 复杂妊娠及其后代以及注射了 重组胰淀素。因此，该项目将提供对复杂机制的独特见解， GDM程序在母亲和后代的心脏重塑。这项研究可能是范式转变， 胰淀素作为这种病理学的关键参与者，这将有助于设计新的治疗策略， 降低GDM母亲及其后代患心脏病的产后风险。