Smooth muscle cell PRDM16 and aortic aneurysm

项目总结/摘要 主动脉瘤（AA）是一种无症状的疾病，如果发生破裂，死亡率很高（65%至85%）。 通过开放或血管内手术进行修复是目前主动脉瘤的唯一治疗选择。没有 这种药物已被批准用于治疗这种毁灭性的疾病。虽然手术干预是有效的 然而，它通常与导致严重发病率的手术并发症有关 甚至死亡率。因此，AA仍然是一种危及生命的疾病。不幸的是， 动脉瘤的发展在很大程度上是未知的，这限制了治疗动脉瘤的药物的发展。 动脉瘤和夹层这突出表明迫切需要更好地了解动脉瘤的形成， 进展PR结构域16（PRDM 16）是一种转录调节因子，在转录调控中起重要作用。 造血细胞、心肌细胞和平滑肌细胞等细胞的确定和发育。 Prdm 16种系或血管平滑肌细胞（VSMC）选择性敲除在小鼠中是胚胎致死的， 强调PRDM 16在VSMC发育过程中的重要性。目前尚不清楚是否 PRDM 16在VSMC中的表达与腹主动脉瘤的发生、发展密切相关。我们的初步数据 表明PRDM 16在AAA患者主动脉中显著减少，PRDM 16 SNP与AAA患者的主动脉中的PRDM 16 SNP相关， 人类AA破裂他莫昔芬诱导的小鼠VSMC选择性Prdm 16敲除导致显著的 AAA病变中弹性蛋白降解增加。这些数据表明，PRDM 16功能的丧失促进了 AAA编队。我们进一步发现PRDM 16负调控转化生长因子的表达， β因子（TGF-β）和A去整合素A金属蛋白酶12（ADAM 12）。TGF-β诱导ADAM 12 表达与细胞凋亡呈正相关。此外，共轭亚油酸（cLA）是一种 ω-3衍生物，作为硝化作用的优先内源性底物。有趣的是， cLA与无机亚硝酸盐（NO2）的相互作用产生内源性硝化cLA（NO2-cLA）。NO2-cLA是下一代 硝基脂肪酸和人体内最丰富的内源性产生。我们的初步数据表明， NO2-cLA稳定PRDM 16蛋白，并在体内防止AAA形成和进展。NO2- cLA以PRDM 16依赖性方式抑制VSMC凋亡和炎症，这是AAA的两个标志。 因此，我们将具体和系统地解决中心假设，即“内生生产 NO2-cLA通过PRDM 16在VSMC中保护AAA的形成和进展”。的具体目标 该建议是：1）确定VSMC中的PRDM 16防止AAA形成和进展; 2） 确定PRDM 16通过抑制TGF-β/ADAM 12信号传导而保护免于VSMC功能障碍; （3）确定VSMC内源性NO_2-cLA的产生通过PRDM 16对AAA的保护作用。 这项工作将PRDM 16定义为AAA的新治疗靶点，并为开发新的治疗靶点奠定基础。 可行的新的口服治疗方法。

Project Summary/Abstract Aortic aneurysm (AA) is an asymptomatic disease with high mortality rate (65% to 85%) if rupture occurs. Repair through open or endovascular surgery is currently the only therapeutic option for aortic aneurysm. No drug has been approved for the treatment of this devastating disease. While surgical intervention is effective in preventing rupture, it is however often associated with surgical complications that result in severe morbidity and even mortality. Thus, AA is still a life-threatening disease. Unfortunately, the mechanisms underlying aneurysm development are largely unknown, which is limiting development of medications for treatment of aneurysms and dissections. This highlights an urgent need for better understanding of aneurysm formation and progression. PR domain containing 16 (PRDM16) is a transcriptional regulator and plays crucial roles in the determination and development of cells including hematopoietic, cardiomyocytes and smooth muscle cells. Prdm16 germline or vascular smooth muscle cell (VSMC) selective knockouts are embryonic lethal in mice, highlighting the importance of PRDM16 in the developmental processes of VSMC. It is not yet known whether PRDM16 in VSMC will affect the development of abdominal aortic aneurysm (AAA). Our preliminary data indicate that PRDM16 is significantly reduced in aorta of AAA patients and the PRDM16 SNP is associated with human AA rupture. Tamoxifen-induced VSMC-selective Prdm16 knockout in mice results in a significant increase in elastin degradation in AAA lesions. These data suggest that loss of PRDM16 function promotes AAA formation. We further uncovered that PRDM16 negatively regulates expression of transforming growth factor β (TGF-β) and A disintegrin A metalloprotease 12 (ADAM12) in VSMC. TGF-β induces ADAM12 expression which is positively correlated with cell apoptosis. Additionally, conjugated linoleic acid (cLA) is an omega-3 derivative that serves as the preferential endogenous substrate of nitration. Interestingly, oral delivery of cLA and inorganic nitrite (NO2) yields endogenous nitrated cLA (NO2-cLA). NO2-cLA is a next generation nitro-fatty acid and the most abundant endogenously produced in humans. Our preliminary data document that NO2-cLA stabilizes PRDM16 protein and protects against AAA formation and progression in vivo. Also, NO2- cLA inhibits VSMC apoptosis and inflammation, two hallmarks of AAA, in a PRDM16-dependent manner. Therefore, we will specifically and systematically address the central hypothesis that “endogenous production of NO2-cLA protects against AAA formation and progression through PRDM16 in VSMC”. The specific aims of this proposal are to: 1) determine that PRDM16 in VSMC prevents AAA formation and progression; 2) determine that PRDM16 protects against VSMC dysfunction through inhibition of TGF-β/ADAM12 signaling; and 3) determine that endogenous production of NO2-cLA protects against AAA through PRDM16 in VSMC. This work will define PRDM16 as a novel therapeutic target for AAA and establish the basis to develop a feasible new oral therapeutic approach..