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Regulation of Vascular Smooth Muscle Calcium by NADPH Redox

NADPH 氧化还原对血管平滑肌钙的调节

基本信息

批准号：
7372575
负责人：
SACHIN A GUPTE
金额：
$ 23.12万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7372575
关键词：
6-Aminonicotinamide 6-phosphogluconate Angiotensin II Aorta Arts Binding Biochemical Biochemical Reaction Bioinformatics Biological Assay Blood Vessels Calcium Calcium Channel Cardiovascular system Cell Survival Cell membrane Cells Co-Immunoprecipitations Commit Complex Contracts Coronary Coronary artery Coupled Culture Techniques Cysteine Cytosol DNA Data Development Diabetes Mellitus Disease Drug Delivery Systems Electrophoresis Environment Enzymes Epiandrosterone Figs - dietary Functional disorder Future Gene Expression Regulation Genes Glucose Glucose-6-Phosphate Glucosephosphate Dehydrogenase Glutathione Glutathione Disulfide Glycolysis Goals Heart Heart failure Human Hydrogen Peroxide Hypertension In Vitro Influentials Ion Channel Ion Channel Protein L-Type Calcium Channels Label Link Localized Lung Measures Mediating Membrane Potentials Metabolic Metabolic Diseases Metabolic Pathway Methods Molecular Biology Techniques Morbidity - disease rate Mus Muscle function Myocardial NADP Organoids Oxidation-Reduction Oxidoreductase PMCA1 protein Pathway interactions Pentosephosphate Pathway Perfusion Personal Satisfaction Phosphorylation Play Process Protein Kinase C Proteins Pulmonary Hypertension Pulmonary artery structure RNA chemical synthesis Radio Radioisotopes Rate Regulation Relaxation Research Research Personnel Resource Sharing Rest Role Sarcoplasmic Reticulum Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Sodium-Calcium Exchanger Testing Thromboxane A2 Tracer Transfection U46619 Vascular Smooth Muscle Vasomotor analog attenuation base cellular imaging channel blockers dehydroepiandrosterone glucose metabolism inhibitor/antagonist innovation inorganic phosphate knock-down mortality mutant mutant mouse model novel novel therapeutics oxidation research study ribose-5-phosphate thioredoxin glutathione reductase voltage

项目摘要

DESCRIPTION (provided by applicant): We have previously provided evidence that the pentose phosphate pathway (PPP)/glucose-6-phosphate dehydrogenase (G6PD) and NADPH redox is involved in modulating contractile function of the coronary (CA) artery. However, the machanism(s) by which G6PD and NADPH modulates contractile function of CA are obscure. Therefore, the primary focus of this proposal will be, to elucidate the signaling pathways involved in mediating the effects of G6PD and NADPH redox on smooth muscle cell L-type Ca2+ currents and CA function. To achieve these goals, we will, in Aim #1 determine if G6PD is active in the sub- cellular fractions of resting and contracting CA, by estimating the rate of glucose oxidation, and the G6PD activity levels by biochemical and radioisotope tracer assays. Furthermore, we will identify mechanism(s) involved in contractile agents-induced-G6PD activation, by investigating the role of PKC and metabolic pathways. In Aim #2, we will determine whether G6PD mediates L-type Ca2+ channel activity, intracellular Ca2+, and vasomotor tone in resting and contracting CA, by examining L-type Ca2+ function, measure intracellular Ca2+ changes and vasomotor function after inhibiting G6PD with pharmacological agents and siRNA transfection, and in G6PD deficient mouse aorta. In Aim #3, we will determine whether glucose-6-phosphate dehydrogenase modulates the L-type Ca2+ channel function, intracellular Ca2+, contraction and redox changes, in CA via direct physical interaction with the ion channel proteins (alpha subunit of CaV1.2), by co-immunoprecipitation, co-localization and in-vitro binding assays. Additionally, we will determine whether direct binding of NADP+ or NADPH to the L-type Ca2+ channel protein inactivates the channel and whether changes in the levels of reduced/oxidized glutathione (GSH) or hydrogen peroxide (H2O2), induced by decrease in NADPH levels (due to the inhibition of G6PD activity), modulates L-type Ca2+ channel function, in smooth muscle cells isolated from coronary and aorta of G6PD deficient mouse. The PPP/G6PD and NADPH redox is up-regulated in diabetes, pulmonary hypertension and heart failure, thereby suggesting a potential role for G6PD and NADPH redox in profoundly impairing the contractile function of blood vessels in these diseases. This study, on completion as anticipated, will prove to be useful in developing novel therapies for the treatment of vascular dysfunction in pulmonary hypertension, diabetes, and heart failure. In the current project, we have undertaken a task to determine whether metabolic changes play a role in the development of circulatory system malfunction, which is a major cause of morbidity and mortality in the USA. This study, therefore, on completion as anticipated, will prove to be useful in developing novel therapies to treat vascular dysfunction in pulmonary hypertension, diabetes, and heart failure.