Abnormal vascular repair in lupus: a link to premature atherosclerosis

描述(由申请人提供)：系统性红斑狼疮(SLE)与过早动脉粥样硬化继发的心血管(CV)事件的发生率增加高达50倍有关。弗雷明翰风险因素不能解释这种增加的倾向，确切的责任机制仍未确定。我们最近提出，系统性红斑狼疮血管损伤的加速是由于内皮细胞损伤(凋亡)和修复的失衡所致。我们推测，I型干扰素(IFN)在诱导SLE异常血管修复中发挥关键作用，并可能在这种疾病中血管损伤和过早动脉粥样硬化的发展中发挥关键作用。具体目的：1.表征I型干扰素在狼疮小鼠系统内皮细胞功能障碍、血管修复和动脉粥样硬化发展中的作用。这将通过将小鼠狼疮模型NZM2328与与I型IFNR基因敲除(KO)小鼠(NZM2318/IFNRKO)杂交的相同品系进行比较来验证。将在这些小鼠中评估内皮依赖和非内皮依赖的血管功能和动脉炎性浸润物的发展。还将评估给予重组干扰素-1是否会加速NZM2328小鼠的内皮功能障碍和促进动脉粥样硬化。2.研究I型干扰素对小鼠系统性红斑狼疮血管生成的影响。通过比较NZM2318和NZM2318/IFNRKO小鼠体内和体外血管生成情况，研究I型干扰素对内皮祖细胞表型和功能的影响。这将通过量化内皮祖细胞、评估其成为成熟内皮细胞的能力、形成和并入血管结构以及合成促血管生成因子来实现。微阵列分析将评估在特定细胞间隔中受NZM2328和NZM2318/IFNRKO中I型IFN影响的EPC基因。将确定受I型IFN影响的血管修复分子通路。3.研究I型干扰素在系统性红斑狼疮血管内皮细胞功能障碍和动脉粥样硬化风险中的作用。密歇根大学已经建立了一个心血管狼疮队列，前瞻性地跟踪SLE患者，检查血管损伤和动脉粥样硬化风险的功能、解剖、细胞和可溶性标记物，以及心血管事件的发展。为了评价I型干扰素在系统性红斑狼疮早产儿CVD发生中的作用，我们将在该队列中建立I型干扰素信号和干扰素-1表达与内皮功能(FMD/NMD)、颈动脉内膜中层厚度(CIMT)、冠状动脉钙化、血清和血管损伤/修复的细胞标志物之间的关系。公共卫生相关性：这项研究的结果将描述促进狼疮患者早期心血管疾病的机制，并可能有助于设计旨在降低这种潜在致命并发症风险的治疗干预措施。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is associated with up to a 50-fold increase in the incidence of cardiovascular (CV) events secondary to premature atherosclerosis. Framingham risk factors do not account for this increased propensity and the exact responsible mechanisms remain uncharacterized. We have recently proposed that accelerated CV damage in SLE is due to an imbalance of endothelial cell damage (apoptosis) and repair. We hypothesize that type I interferons (IFNs) play a crucial role in the induction of abnormal vascular repair in SLE and, potentially in the development of vascular damage and premature atherosclerosis in this disease. SPECIFIC AIMS: 1. Characterize the role of type I IFNs on endothelial dysfunction, vascular repair and atherosclerosis development in lupus murine systems. This will be tested by comparing the murine lupus model NZM2328 with the same strain crossed to type I IFNR knock-out (KO) mice (NZM2318/IFNRKO). Endothelium-dependent and independent vascular function and development of arterial inflammatory infiltrates will be evaluated in these mice. Whether administration of recombinant IFN-1 accelerates endothelial dysfunction and promotes atherosclerosis in NZM2328 mice will also be evaluated. 2. Characterize the angiogenenic pathways affected by type I IFNs in murine SLE. The role of type I IFNs on phenotype and function of endothelial progenitor cells (EPCs) will be studied by comparing vasculogenesis in vitro and in vivo on NZM2318 and NZM2318/IFNRKO mice. This will be performed by quantifying EPCs, assessing their capacity to become mature ECs, form and incorporate into vascular structures, and synthesize proangiogenic factors. Microarray analysis will assess the EPC genes affected by type I IFNs in NZM2328 and NZM2318/IFNRKO in specific cellular compartments. Vascular repair molecular pathways that are affected by type I IFNs will be identified. 3. Characterize the role of type I IFNs in endothelial dysfunction and atherosclerosis risk in SLE. The University of Michigan has established a Cardiovascular Lupus Cohort which follows SLE patients prospectively to examine functional, anatomical, cellular and soluble markers of vascular damage and atherosclerotic risk, and the development of CV events. To assess the role of type I IFNs in the development of premature CVD in SLE, the association of type I IFN signatures and IFN-1 expression with endothelial function (FMD/NMD), carotid intimal medial thickness (CIMT), coronary calcification, serum and cellular markers of vascular damage/ repair will be established in this cohort. PUBLIC HEALTH RELEVANCE: The results from this study will characterize mechanisms that promote early cardiovascular disease in patients with lupus and could contribute to the design of therapeutic interventions aimed at decreasing the risk of this potentially fatal complication.