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）与继发于过早动脉粥样硬化的心血管（CV）事件发生率增加50倍相关。脆性风险因素不能解释这种增加的倾向，确切的责任机制仍然没有特征。我们最近提出，加速CV损伤SLE是由于内皮细胞损伤（凋亡）和修复的不平衡。我们推测，I型干扰素（IFN）在诱导SLE异常血管修复中起着至关重要的作用，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作用。具体目标：1.描述I型干扰素对狼疮鼠系统内皮功能障碍、血管修复和动脉粥样硬化发展的作用。这将通过比较鼠狼疮模型NZM 2328与与I型IFNR敲除（KO）小鼠（NZM 2318/IFNRKO）杂交的相同品系进行测试。将在这些小鼠中评价内皮依赖性和非依赖性血管功能以及动脉炎性浸润的发展。还将评估施用重组IFN-1是否加速NZM 2328小鼠中的内皮功能障碍并促进动脉粥样硬化。2.描述I型干扰素对小鼠SLE血管生成途径的影响。通过比较NZM 2318和NZM 2318/IFNRKO小鼠体外和体内血管发生，研究I型IFN对内皮祖细胞（EPCs）表型和功能的作用。这将通过量化EPC，评估其成为成熟EC的能力，形成并整合到血管结构中，以及合成促血管生成因子来进行。微阵列分析将评估NZM 2328和NZM 2318/IFNRKO中特定细胞区室中受I型IFN影响的EPC基因。将鉴定受I型IFN影响的血管修复分子途径。3.描述I型干扰素在SLE内皮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，前瞻性地随访SLE患者，以检查血管损伤和动脉粥样硬化风险的功能、解剖、细胞和可溶性标志物，以及CV事件的发生。为了评估I型IFN在SLE早发CVD中的作用，将在该队列中建立I型IFN特征和IFN-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、血管损伤/修复的血清和细胞标志物的关联。公共卫生相关性：这项研究的结果将表征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.