Endothelial Inflammasomes in Coronary Microcirculation -Beyond Inflammation

冠状动脉微循环中的内皮炎症小体 - 超越炎症

• 批准号: 8671737
• 负责人: Yang Zhang
• 金额: $ 38.13万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671737
• 关键词: Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arteries; Atherosclerosis; Blood; Blood Vessels; Cardiovascular Diseases; Caspase-1; Cause of Death; Cells; Cholesterol; Coronary; Coronary artery; Development; Diabetes Mellitus; Dyslipidemias; Endothelial Cells; Endothelium; Homing; Hyperhomocysteinemia; Hypertension; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-18; Interleukins; Link; Lysosomes; Mammalian Cell; Mediating; Microcirculation; Molecular; Mus; NADP; Natural regeneration; Obesity; Pathogenesis; Pathway interactions; Patients; Pattern; Permeability; Plasma; Prevention; Recruitment Activity; Reporting; Right-On; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Staging; Stem cells; T-Lymphocyte; Testing; Therapeutic; Time; Vascular Diseases; Vascular Permeabilities; Vasodilation; Work; adipokines; atherogenesis; base; cardiovascular disorder prevention; clinical practice; cytokine; endothelial dysfunction; in vivo; insight; interest; migration; novel; public health relevance; repaired; response; treatment strategy; vascular endothelial cadherin-2; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Despite the recognized role of inflammation in cardiovascular diseases including atherosclerosis, this role may not be an initiating or essential mechanism in atherogenesis because current clinical practice is unsuccessful or has low efficiency if only using anti-inflammatory therapeutic strategy in treatment and prevention of cardiovascular diseases such as atherosclerosis. Endothelial dysfunction is the very early stage of many cardiovascular diseases including atherosclerosis. However, it remains unknown what mechanism can initiate endothelial dysfunction at early stages prior to or during inflammation. Recent studies have shown that Nlrp3 inflammasomes is a major intracellular molecular machinery to switch on the inflammatory response. Interestingly, our preliminary studies demonstrated that the formation and activation of Nlrp3 inflammasomes in endothelial cells were observed in response to danger factors including cholesterol crystal and visfatin (an injurious adipokine) and that some interesting early direct effects beyond inflammation were also shown to be induced by Nlrp3 inflammasome activation such as impaired endothelium-dependent vasodilation, enhanced vascular permeability or cell infiltration, and pathogenic homing or differentiation of endothelial progenitor cells. This may represent a novel pathogenic mechanism of inflammasome activation beyond inflammation. Thus, we hypothesize that beyond inflammation, activation of endothelial inflammasomes by endogenous danger signals directly induces endothelial dysfunction and vascular injury in coronary arteries. To test this hypothesis, we proposed 3 specific aims. Aim 1 will determine whether Nlrp3 inflammasomes are formed and activated in response to danger factors such as cholesterol crystal and visfatin and which non-inflammatory effects are induced by activated Nlrp3 inflammasomes in addition to inflammatory response using coronary arterial ECs (CAECs) from Nlrp3-/- and Nlrp3+/+ mice. Aim 2 will determine whether activated endothelial Nlrp3 inflammasomes contribute to coronary endothelial dysfunction and vascular injury in vivo independent of inflammation using Nlrp3-/- mice and their wild type littermates. Aim 3 will explore how endothelial Nlrp3 inflammasomes are activated to produce coronary vascular injurious actions beyond inflammation and which inflammasome-activating pathway mainly produces the non-inflammatory effects using primary culture of CAECs and Nlrp3-/- mice and their littermates. The findings from this grant proposal will for the first time explore the non-inflammatory role of inflammasome in coronary endothelial dysfunction and vascular injury and define the early, initiating mechanisms mediating the response of CAECs to endogenous danger signals such as increased plasma cholesterol, cytokine or adipokines, which will provide new insights into the pathogenesis of vascular disease associated with endothelial dysfunction and microvascular injury.

描述（由申请人提供）：尽管炎症在包括动脉粥样硬化在内的心血管疾病中具有公认的作用，但这种作用可能并不是动脉粥样硬化中的启动或基本机制，因为当前的临床实践失败或仅使用抗炎治疗策略在治疗和预防心脏血管内疾病的抗炎治疗策略之类的效率下。内皮功能障碍是许多心血管疾病（包括动脉粥样硬化）的早期阶段。但是，尚不清楚哪种机制可以在炎症之前或期间早期阶段引发内皮功能障碍。最近的研究表明，NLRP3炎症体是开启炎症反应的主要细胞内分子机械。有趣的是，我们的初步研究表明，在响应包括胆固醇晶体和维斯法汀（有害的脂肪因子）（有害的脂肪因子）在内的危险因素中观察到内皮细胞中NLRP3炎症的形成和激活，并且还表明，NLRP3炎症的激活源具有Impramase Actipation in Impaintiantimation in Impaintiantimation in Impaintiantimation in vermantiation nlr3渗透性或细胞浸润，以及内皮祖细胞的致病性归因或分化。这可能代表了超出炎症的炎性体激活的新型致病机制。因此，我们假设除炎症外，内源性危险信号对内皮炎症的激活直接引起冠状动脉动脉内皮功能障碍和血管损伤。为了检验这一假设，我们提出了3个具体目标。 AIM 1将确定是否形成了NLRP3炎性症，并激活诸如胆固醇晶体和粘蛋白等危险因素，以及使用NLRP3的NLRP3冠状动脉ECS（CAECS）炎性反应，除了使用冠状动脉反应（使用冠状动脉反应）外，激活的NLRP3炎性症诱导了哪些非炎症作用。 AIM 2将确定活化的内皮NLRP3炎症是否有助于使用NLRP3 - / - 小鼠及其野生型同窝小鼠在体内有助于冠状动脉内皮功能障碍和血管损伤。 AIM 3将探讨如何激活内皮NLRP3炎症，从而产生冠状动脉血管损害作用，而超越炎症，并且炎症体激活途径主要使用CAEC和NLRP3 - / - / - 小鼠及其同els的原发性培养产生非炎症效应。 The findings from this grant proposal will for the first time explore the non-inflammatory role of inflammasome in coronary endothelial dysfunction and vascular injury and define the early, initiating mechanisms mediating the response of CAECs to endogenous danger signals such as increased plasma cholesterol, cytokine or adipokines, which will provide new insights into the pathogenesis of vascular disease associated with endothelial功能障碍和微血管损伤。