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）：尽管炎症在心血管疾病（包括动脉粥样硬化）中的作用是公认的，但这种作用可能不是动脉粥样硬化形成的起始或必要机制，因为如果仅使用抗炎治疗策略治疗和预防心血管疾病（如动脉粥样硬化），目前的临床实践是不成功的或效率低。内皮功能障碍是包括动脉粥样硬化在内的许多心血管疾病的早期阶段。然而，在炎症之前或炎症期间的早期阶段，什么机制可以引发内皮功能障碍仍然是未知的。最近的研究表明，Nlrp 3炎性小体是一种主要的细胞内分子机制，以开关的炎症反应。有趣的是，我们的初步研究表明，内皮细胞中Nlrp 3炎性体的形成和激活是对胆固醇晶体和内脂素等危险因素的反应（一种有害的脂肪因子），并且还显示出炎症以外的一些令人感兴趣的早期直接作用是由Nlrp 3炎性体活化诱导的，例如内皮依赖性血管舒张受损，血管通透性或细胞浸润增强，以及内皮祖细胞的致病性归巢或分化。这可能代表了炎症以外的炎性小体激活的一种新的致病机制。因此，我们假设，除了炎症，内源性危险信号激活内皮炎性小体直接诱导内皮功能障碍和血管损伤的冠状动脉。为了验证这一假设，我们提出了三个具体目标。目的1将使用来自Nlrp 3-/-和Nlrp 3 +/+小鼠的冠状动脉EC（CAEC）来确定Nlrp 3炎性体是否响应于危险因素如胆固醇结晶和内脂素而形成和活化，以及活化的Nlrp 3炎性体除了诱导炎性反应之外还诱导哪些非炎性作用。目的2将使用Nlrp 3-/-小鼠和它们的野生型同窝出生仔确定活化的内皮Nlrp 3炎性体是否有助于体内冠状动脉内皮功能障碍和血管损伤，而不依赖于炎症。目的3利用原代培养的CAECs和Nlrp 3-/-小鼠及其同窝仔，探讨内皮Nlrp 3炎性小体是如何被激活产生炎症以外的冠状动脉血管损伤作用的，以及哪条炎性小体激活途径主要产生非炎症作用。这项资助提案的发现将首次探索炎性小体在冠状动脉内皮功能障碍和血管损伤中的非炎症作用，并确定介导CAEC对内源性危险信号（如血浆胆固醇增加，细胞因子或脂肪因子）反应的早期启动机制，这将为与内皮功能障碍和微血管损伤相关的血管疾病的发病机制提供新的见解。