在基于结构的药物发现中准GPR39可降低Ang II诱导的高血压
Dongxu Hua1,2,3, Wanlin Huang1, Qiyang Xie2,3
1Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
Communications biology
|November 5, 2024
概括
消灭G蛋白结合受体39 (GPR39) 通过减少血管损伤减轻了高血压. 用小分子联体向GPR39也改善了血管功能,提供了新的治疗策略.
科学领域:
- 心血管生物学 心血管生物学
- 分子医学是分子医学.
- 高血压研究 高血压研究
背景情况:
- 内皮依赖的血管损伤是血管激素II (Ang II) 诱导的高血压的核心.
- 在这个过程中G蛋白结合受体39 (GPR39) 的作用仍然不清楚.
研究的目的:
- 研究GPR39在Ang II诱导的高血压中的作用和机制.
- 识别和验证针对GPR39.9的潜在治疗策略.
主要方法:
- GPR39淘汰赛 (KO) 的小鼠接受了Ang II的管理.
- 评估了血管功能,纤维化,炎症,氧化应激和亡.
- 分析了NOD类受体蛋白3 (Nlrp3) 的表达.
- 基于结构的虚拟选确定了一个GPR39连接体 (Z1780628919).
主要成果:
- 在高血压模型中,GPR39表达升高.
- 摘除GPR39改善了血管纤维化,改善了血管扩张,并减少了炎症,氧化应激和亡.
- 缺乏GPR39会降低NLRP3的表达,而NLRP3的激活会扭转GPR39的KO效果.
- GPR39的配体Z1780628919表现出抗高血压作用和改善血管功能.
结论:
- GPR39在Ang II诱导的高血压发病过程中发挥着关键作用.
- 通过抑制GPR39抑制NLRP3的下调是其保护作用的基础.
- GPR39及其连接物Z1780628919是高血压的有希望的治疗点.
相关概念视频
01:30Antihypertensive Drugs: Angiotensin II Receptor Blockers
590
In the renin-angiotensin-aldosterone system, a hormone called angiotensin II plays a crucial role. It binds to the AT1 receptors in vascular smooth muscles coupled with Gq proteins. The activation of these receptors activates an enzyme called phospholipase C, which releases two molecules: inositol trisphosphate and diacylglycerol. These molecules cause a chain reaction that leads to the phosphorylation of myosin light chains and promotes interaction between actin and myosin, leading to smooth...
590
01:25Antihypertensive Drugs: Direct Renin Inhibitors
498
The renin-angiotensin-aldosterone system (RAAS) is an intricate physiological pathway involving numerous enzymes and hormones, including renin, angiotensin-converting enzyme (ACE), angiotensin I and II, and aldosterone. Imbalances within this system increase the production of angiotensin II and aldosterone. Increased angiotensin II levels promote vasoconstriction and blood pressure elevation. Concurrently, higher aldosterone levels stimulate sodium and water reabsorption in the kidneys,...
498
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
482
Angiotensin-converting enzyme (ACE), a vital component of the renin-angiotensin-aldosterone system, is abundant in lung endothelial cells. ACE converts the inactive decapeptide, angiotensin I, into the active octapeptide, angiotensin II. This potent vasoconstrictor narrows blood vessels, increasing resistance to blood flow and elevating blood pressure. Angiotensin II also stimulates aldosterone production, encouraging kidney cells to reabsorb more sodium and water from urine, thereby increasing...
482
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
391
The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, and inhibiting the RAAS is a pharmacological target in heart failure management. As a result, neurohumoral modulation is a crucial treatment principle for managing heart failure. This approach involves using medications like ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and neutral...
391
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.4K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.4K
01:15G Protein-coupled Receptors
11.4K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
11.4K