STIM1 and its role in regulating cardiac metabolism

STIM1及其在心脏代谢中的调节作用

• 批准号: 10371868
• 负责人: JOHN C CHATHAM
• 金额: $ 54.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371868
• 关键词: Adult; Adverse effects; Age; Amino Acids; Attenuated; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cell membrane; Cells; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Elements; Energy Metabolism; Etiology; Eukaryotic Cell; Event; Exhibits; Fasting; Fatty Acids; Foundations; Functional disorder; GLUT 4 protein; Genetic Transcription; Glucose; Glycolysis; Goals; Heart; Heart Diseases; Heart failure; Homeostasis; Hormones; Hypertrophy; Impairment; Incidence; Ketone Bodies; Knockout Mice; Knowledge; Lipids; Metabolic; Metabolism; Mitochondria; Molecular; Pathology; Pathway interactions; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Production; Prognosis; Proteins; Pyruvate; Quality Control; Recurrence; Regulation; Reporting; Repression; Role; STIM1 gene; Signal Pathway; Signal Transduction; Survival Rate; System; Testing; Up-Regulation; Workload; calcium metabolism; cardiogenesis; diabetic cardiomyopathy; effective therapy; feeding; flexibility; glucose metabolism; heart function; heart metabolism; improved; insight; insulin signaling; metabolic phenotype; mortality; novel therapeutics; oxidation; pressure; pyruvate dehydrogenase; response; restoration

Mortality rates associated with cardiovascular disease have decreased significantly; however, the incidence of heart failure continues to grow and 5-year survival rates remain at ~50%, underscoring the need to improve our knowledge of the molecular underpinnings of this disease. The heart requires a high level of metabolic flexibility to enable it to continuously adapt to changing workload demands throughout the day. Substrate availability and hormone levels also fluctuate with fasting/feeding cycles, further demanding cardiac metabolic flexibility. Loss of cardiac metabolic flexibility is a recurrent feature of cardiac disease, observed during hypertrophy, heart failure and diabetic cardiomyopathy. Similarly, dysregulation of Ca2+ homeostasis is a common element underlying the etiology of many cardiac diseases. Calcium is an established regulator of cardiac metabolism and mitochondrial function, through direct allosteric interactions, posttranslational modifications, and transcriptional events. However, despite established roles of Ca2+ in regulating cardiac energy metabolism, the specific Ca2+ handling pathways involved are not well characterized and their role in maintaining metabolic flexibility is not known. STromal Interaction Molecule-1 (STIM1) is a ubiquitously expressed and highly evolutionarily conserved protein located in the ER/SR that is responsible for regulating diverse Ca2+ signaling pathways in non-excitable cells and is recognized as a core element of all mammalian Ca2+ signaling systems. Despite discovery of STIM1 in the heart approximately 20 years ago, our knowledge about the physiological role of STIM1 in adult cardiomyocytes remains unclear and controversial. We recently reported that cardiomyocyte deletion of STIM1 (crSTIM1-KO) precipitates contractile dysfunction and dilated cardiomyopathy by 36 weeks of age. In young crSTIM1-KO mice prior to onset of contractile dysfunction there was impaired glucose metabolism and insulin signaling combined with increased lipid accumulation and an upregulation of lipogenic proteins. This metabolic phenotype is very similar to the cardiac metabolic signature observed during diabetes, a well characterized example of metabolic inflexibility. Collectively, these observations have led to the hypothesis that STIM1 is a previously unrecognized regulator of cardiac metabolism and mitochondrial function and that decreased STIM1 contributes to the adverse effects of diabetes on the heart. To test this hypothesis, we will 1) Define fully the extent to which STIM1 regulates cardiac metabolism; 2) Establish the mechanisms by which STIM1 influences mitochondrial function in the heart and 3) Determine how diabetes regulates STIM1 levels and whether loss of STIM1 contributes to the adverse effects of diabetes on the heart. The successful completion of this proposal will provide significant new insights into the role of STIM1 in regulating cardiac metabolism and mitochondrial function and provide the foundation for improved understanding regarding the contribution of STIM1 dysregulation to cardiac metabolic inflexibility and contractile dysfunction during disease states.

与心血管疾病有关的死亡率显著下降；然而，发病率