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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.

摘要