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Mechanism of blood pressure lowering by fatty acid nutraceuticals

脂肪酸保健品降血压的机制

基本信息

批准号：
9918934
负责人：
TOSHINORI HOSHI
金额：
$ 56.35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918934
关键词：
Affinity Amino Acids Animals Antihypertensive Agents Binding Biochemical Biophysics Blood Pressure Blood Pressure Monitors Calcium Carbon Cells Chemicals Clinical Clupeidae Complex Development Diet Docosahexaenoic Acids Eicosapentaenoic Acid Electrophysiology (science)Energy Transfer Fatty Acids Fish Oils Fishes Food Foundations Free Energy Head Health Health Promotion Human Hydrogen Bonding Interferometry Ion Channel Ion Channel Protein Ions Knock-in Mouse Length Location Measures Mediating Methods Modeling Molecular Molecular Conformation Molecular Target Motion Mus Mutagenesis Myography Nature Nutraceutical Omega-3 Fatty Acids Outcome Outcomes Research Patients Pharmacologic Substance Physiological Positioning Attribute Potassium Proteins Public Health Pump Randomized Research Role Rotation Salmon Scombridae Side Smooth Muscle Myocytes Solid Structure Tail Telemetry Testing Tyrosine Vascular Smooth Muscle Voltage-Gated Potassium Channel arctic environment awake base blood pressure reduction blood pressure regulation carboxylate control trial design experimental study in vivo large-conductance calcium-activated potassium channels pi bond programs response voltage

项目摘要

Project Summary Long-‐‑chain polyunsaturated omega-‐‑3 fatty acids, such as docosahexaenoic acid (DHA) with a 22-‐‑carbon chain, are found abundantly in oily fish including anchovy, herring, mackerel, and salmon. These omega-‐‑3 fatty acids are widely thought to have multiple health-‐‑promoting effects. Evidence suggests that DHA decreases blood pressure, especially in hypertensive patients. We hypothesize that the hypotensive action of DHA is mediated by its stimulatory effect on large-‐‑conductance calcium and voltage-‐‑gated potassium (Slo1 BK) channels important in blood pressure regulation. The research program proposed here will provide molecular and atomic basis of the hypotensive action of DHA involving Slo1 BK channels using biophysical, biochemical, and whole-‐‑animal methods. We postulate that a hydrogen bond between a tyrosine residue in the S6 segment of the channel and the carboxylate group is critical in destabilizing the closed conformation of the ion conduction gate and this interaction underlies the whole-‐‑animal hypertensive action. Using the physicochemical principles elucidated, we will rationally design, synthesize and test fatty-‐‑acid activators of Slo1 BK channels. The anticipated outcome of the research program has potential to explain blood pressure regulation of whole animals based on the hydrogen bonds formed between specific tyrosine residues of the Slo1 BK channel and DHA and provide a solid mechanistic foundation for discovery and development of pharmaceuticals and nutraceuticals for blood pressure management.

项目摘要长链多不饱和omega-3脂肪酸，如二十二碳六烯酸（DHA）脂肪酸链，在多油的鱼类，包括鲱鱼，鲭鱼和鲑鱼中大量发现。这些欧米伽-β-3 脂肪酸被广泛认为具有多种促进健康的作用。有证据表明，降低血压，特别是在高血压患者中。我们假设， DHA的作用是通过其对大电导钙和电压门控钾的刺激作用介导的 (Slo1 BK）通道在血压调节中的重要性。这里提出的研究计划将提供DHA涉及Slo 1 BK通道的舒张作用的分子和原子基础，生物物理学、生物化学和整体动物方法。我们假设，在通道的S6段和羧酸基团中的酪氨酸残基是使通道不稳定的关键。离子传导门的闭合构象和这种相互作用是整个动物的基础本论文将利用所阐明的理化原理，合理设计、合成并测试Slo 1 BK通道的脂肪酸激活剂。该研究计划的预期成果基于氢键形成的解释整个动物血压调节的潜力 Slo 1 BK通道的特定酪氨酸残基和DHA之间的相互作用，并提供了一个坚实的机制，血压药物和保健品发现和开发基金会管理