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.

摘要 妊娠期糖尿病(GDM)增加了母亲患心血管疾病的风险 以及后代。最近的一项基于人群的大型前瞻性研究(CARDIA)发现，GDM是独立的 与晚年的心肌肥大和心脏功能受损有关。与这一发现一致，我们的 初步数据显示心肌肥厚和激活钙依赖的转录信号2 在妊娠合并妊娠期糖尿病的雌性大鼠怀孕几个月后。尽管高血糖通常被认为是 作为关键的调解人，许多研究报告称，即使在 母亲的血糖控制良好。因此，额外的机制促进新陈代谢和心血管 妊娠期糖尿病的功能障碍。我们之前证明了胰淀素的重要作用，胰淀素是一种胰腺激素， 心脏淀粉样蛋白的特性及其分泌与胰岛素的平行增加 2型糖尿病所致的重塑和功能障碍。此外，我们还发现胰淀素能激活钙离子。 心肌细胞中的依赖转录信号。我们的初步研究表明， 患有妊娠期糖尿病的雌性大鼠及其后代的血液。基于这些发现，我们假设GDM 钙依赖性激活促进母子代心脏病理性重构 由全身性胰淀素代谢紊乱触发的肥大信号。为了检验这一总体假设，我们 Will i)确定GDM诱导的心脏病理重塑的分子机制， Ii)探讨妊娠期糖尿病患者胰淀素-心肌细胞间的相互作用，以及iii)评估高淀粉血症对 妊娠诱导的心脏重构在没有其他与妊娠期糖尿病相关的代谢改变时。 实验将结合心脏结构和功能的活体评估和药物治疗 通过对正常和妊娠期糖尿病雌性大鼠的移植心脏和分离的心肌细胞的测量，发现正常和GDM雌性大鼠在体心脏和分离的心肌细胞。 合并症妊娠及其后代和妊娠胰淀素-KO雌性 重组胰淀素。因此，该项目将提供对复杂机制的独特见解 妊娠期糖尿病计划母亲和后代的心脏重塑。这项研究可能是范式的转变，因为它断言 胰淀素代谢紊乱是这一病理过程中的关键因素，这将有助于设计新的治疗策略。 降低妊娠期糖尿病母亲及其后代的产后心脏病风险。