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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：
9212439
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212439
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 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 Muscle Cells Mutagenesis Myography Nature Nutraceutical Omega-3 Fatty Acids Outcome Outcomes Research Patients Pharmacologic Substance Physiological Positioning Attribute Potassium Proteins Public Health Pump Randomized Controlled Trials Research Role Rotation Salmon Scombridae Side Solid Tail Telemetry Testing Tyrosine Vascular Smooth Muscle Voltage-Gated Potassium Channel arctic environment awake base blood pressure reduction blood pressure regulation carboxylate 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，例如具有 22 个碳原子的二十二碳六烯酸 (DHA) 链，大量存在于油性鱼类中，包括凤尾鱼、鲱鱼、鲭鱼和鲑鱼。这些 omega-‐‐3 人们普遍认为脂肪酸具有多种促进健康的作用。有证据表明 DHA 降低血压，尤其是高血压患者。我们假设降压作用 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) 通道对血压调节很重要。这里提出的研究计划将使用 Slo1 BK 通道提供 DHA 降压作用的分子和原子基础生物物理、生物化学和整体动物方法。我们假设a之间存在氢键通道 S6 段中的酪氨酸残基和羧酸基团对于破坏通道的稳定性至关重要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高血压行为。利用阐明的物理化学原理，我们将合理设计、合成并测试 Slo1 BK 通道的脂肪酸激活剂。研究计划的预期结果有可能根据形成的氢键解释整个动物的血压调节 Slo1 BK 通道的特定酪氨酸残基和 DHA 之间的相互作用，并提供可靠的机制发现和开发血压药物和营养保健品的基础管理。