循环氧化原酶-2衍生的前环素通过抑制组织因子以一种Sirtuin-1依赖的方式调节动脉血栓的形成
Silvia S Barbieri1, Patrizia Amadio, Sara Gianellini
1Centro Cardiologico Monzino, IRCCS, Via Parea 4, 20138 Milano, Italy. silviabarbieri@yahoo.com
Circulation
|August 7, 2012
概括
选择性循环氧化酶-2 (COX-2) 抑制剂增加了血栓形成的风险. 消除COX-2通过减少前环素和Sirtuin-1 (SIRT1),增加组织因子 (TF) 来增强血栓形成.
科学领域:
- 心血管生物学 心血管生物学
- 血栓形成的研究研究
- 药理学 药理学是指药理学的学科.
背景情况:
- 选择性循环氧化酶-2 (COX-2) 抑制剂与心肌梗塞和血栓事件的增加有关.
- 这些血栓形成风险背后的确切机制仍然不完全理解.
研究的目的:
- 阐明COX-2影响动脉血栓形成的机制.
- 调查前环素,过氧酶增殖器激活受体-δ (PPARδ) 和Sirtuin-1 (SIRT1) 在COX-2-介导的血栓形成中的作用.
主要方法:
- 铁化物诱导的动脉血栓形成在COX-2淘汰和野生类型小鼠中的比较.
- 交叉输血实验以评估血小板贡献.
- 对前环素合成酶,氧酶增殖器激活受体-δ,Sirtuin-1 (SIRT1) 和组织因子 (TF) 的表达和活性进行分析.
- 药理学调节前环素和PPARδ通路,以及SIRT1抑制/激活.
主要成果:
- 与野生型小鼠相比,COX-2淘汰小鼠的动脉血栓形成显著增加.
- 脱离COX-2导致前环和SIRT1的表达减少,从而增加组织因子 (TF) 开始凝血.
- простациклин 或 PPARδ 激动作用逆转了 COX-2 淘汰赛小鼠中的原血栓现象,而它们在野生型小鼠中的对抗作用促进了血栓形成.
- 抑制SIRT1增加了TF活性和血栓形成,而SIRT1激活减少了TF活性和COX-2淘汰小鼠的前血栓状态.
结论:
- простациклин/PPARδ途径调节SIRT1和TF,代表了一种控制动脉血栓形成的新机制.
- 通过这些途径准SIRT1和TF可能为与COX-2抑制剂相关的动脉血并发症提供治疗策略.
相关概念视频
01:30Anticoagulant Drugs: Low-Molecular-Weight Heparins
Hemostasis is a crucial process that prevents excessive blood loss from damaged blood vessels. It involves various mechanisms such as vasoconstriction, platelet adhesion and activation, and fibrin formation. The importance of each mechanism depends on the type of vessel injury. In contrast, thrombosis is the abnormal formation of a blood clot within the blood vessels, leading to potential complications if the clot obstructs blood flow. Thrombosis can be caused by increased coagulability of the...
01:20Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors
Antiplatelet drugs emerge as frontline defenders against the insidious threat of thromboembolic diseases, where abnormal clots obstruct vital blood vessels. These drugs stand as bulwarks, inhibiting platelet aggregation and clot formation, thereby mitigating the risk of life-threatening conditions like myocardial infarction, coronary artery disease, and thrombotic strokes.
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
01:22Formation of the Platelet Plug
The platelet phase, the second stage of hemostasis, commences around 15-20 seconds after an injury. It follows and overlaps with the vascular phase, during which blood vessels constrict to minimize blood loss.
As the injured blood vessel contracts, endothelial cells undergo contraction, revealing collagen fibers in the basement membrane and underlying connective tissue. Furthermore, the plasma membrane of endothelial cells becomes adhesive, preparing the site for platelet adhesion. Platelets...
As the injured blood vessel contracts, endothelial cells undergo contraction, revealing collagen fibers in the basement membrane and underlying connective tissue. Furthermore, the plasma membrane of endothelial cells becomes adhesive, preparing the site for platelet adhesion. Platelets...
01:20Extrinsic and Intrinsic Pathways of Hemostasis
Blood clotting or coagulation involves extrinsic and intrinsic pathways, which ultimately merge into the common pathway, forming a fibrin clot.
The Extrinsic Pathway
The extrinsic pathway of coagulation is typically initiated by tissue damage that exposes blood to tissue factor (TF), a protein released by the damaged tissue cells outside the blood vessels—this interaction with TF triggers biochemical reactions involving specific clotting factors. The key player here is Factor VII, which forms a...
The Extrinsic Pathway
The extrinsic pathway of coagulation is typically initiated by tissue damage that exposes blood to tissue factor (TF), a protein released by the damaged tissue cells outside the blood vessels—this interaction with TF triggers biochemical reactions involving specific clotting factors. The key player here is Factor VII, which forms a...
01:16Clot Retraction and Fibrinolysis
After a fibrin clot is formed, the next step is clot retraction, a vital process facilitated by platelet contractile proteins, such as actin and myosin. These proteins pull the fibrin strands closer together and condense the clot. This action reduces the size of the clot, creating a smaller, denser structure that effectively seals off the damaged vessel. Clot retraction consolidates the clot and helps with wound healing by bringing the edges of the damaged blood vessel closer together.
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
Prostacyclin receptor agonists are a class of therapeutic agents integral to managing pulmonary arterial hypertension (PAH). These drugs operate by mimicking the action of prostaglandin I2, or PGI2, a naturally occurring compound in the body.
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...