Nitro-oleic acid (NO2-OA) reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome.
Nitro-oleic acid (NO2-OA) reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome.
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DOI：
10.1093/cvr/cvab256
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发表时间：
2021-07
影响因子：
10.8
通讯作者：
F. Nettersheim;Julian Lemties;S. Braumann;S. Geißen;S. Bokredenghel;Richard J. Nies;Alexander Hof;H. Winkels;B. Freeman;A. Klinke;V. Rudolph;S. Baldus;D. Mehrkens;M. Mollenhauer;Matti Adam
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作者：
F. Nettersheim;Julian Lemties;S. Braumann;S. Geißen;S. Bokredenghel;Richard J. Nies;Alexander Hof;H. Winkels;B. Freeman;A. Klinke;V. Rudolph;S. Baldus;D. Mehrkens;M. Mollenhauer;Matti Adam
目的马凡氏综合征（MFS）是一种由原纤维蛋白-1基因突变引起的结缔组织疾病。它与胸主动脉瘤的形成有关，由于主动脉破裂或夹层，胸主动脉瘤可能是危及生命的疾病。已确定由细胞外信号调节激酶1/2（ERK 1/2）激活介导的过度非经典转化生长因子β信号传导以及诱导型一氧化氮合酶（NOS 2）依赖性一氧化氮产生通过诱导弹性蛋白断裂和平滑肌细胞凋亡驱动MFS中的主动脉病理。尽管在动物研究中取得了令人鼓舞的结果，但批准用于MFS相关主动脉疾病患者临床使用的特定药理学干预措施很少。硝基油酸（NO2-OA）是一种内源性信号调节剂，可作为口服化合物使用，并已显示在不同疾病模型中抑制ERK 1/2激活和NOS 2表达，从而发挥有希望的治疗作用。在这项研究中，我们研究了NO2-OA是否减少MFS的主动脉扩张。方法和结果8周龄MFS（Fbn 1C 1041 G/+）小鼠经皮下植入微型渗透泵，给予NO2-OA或溶剂4周。超声心动图显示MFS小鼠进行性升主动脉扩张和壁硬化，NO2-OA治疗显著减弱。这种保护作用是通过抑制主动脉ERK 1/2、Smad 2以及核因子κ B的过度活化和随后的基质金属蛋白酶2、细胞凋亡和胶原沉积引起的弹性蛋白断裂的衰减来介导的。重要的是，NO2-OA在MFS中的治疗功效通过证明其在用血管紧张素II激发的Fbn 1C 1041 G/+小鼠中减少致死性主动脉并发症的能力而得到进一步强调。结论NO2-OA通过调节已建立的疾病介导途径明显抑制MFS主动脉扩张的进展，因此值得进一步研究其作为治疗该疾病的治疗剂的应用。胸主动脉瘤形成是马凡综合征的主要危及生命的并发症，马凡综合征是一种相对常见的遗传性结缔组织疾病。虽然已经确定了各种潜在的治疗靶点，但仍然无法获得特定的药理学治疗选择。在这项研究中，我们证明了硝基油酸通过抑制细胞外信号调节激酶1/2、Smad 2以及核因子κ B过度活化来减少马凡氏综合征患者的升主动脉弹性蛋白断裂、细胞凋亡和纤维化重构，从而减轻动脉瘤形成。因此，已开发为口服化合物的硝基油酸成为Marfan相关主动脉疾病的潜在治疗选择。
AIMS Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular-signal regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. METHODS AND RESULTS Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for four weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+mice challenged with Angiotensin II. CONCLUSION NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition. TRANSLATIONAL PERSPECTIVE Thoracic aortic aneurysm formation is the major life-threatening complication of Marfan syndrome, a relatively common genetic connective tissue disorder. Although various potential therapeutic targets have been identified, specific pharmacological treatment options are still unavailable. In this study, we demonstrate that Nitro-oleic acid reduces ascending aortic elastin fragmentation, apoptosis, and fibrotic remodelling in Marfan syndrome through inhibition of extracellular-signal regulated kinases 1/2, Smad2 as well as nuclear factor kappa B overactivation and thereby mitigates aneurysm formation. Thus, Nitro-oleic acid, which has been developed as an oral compound, emerges as a potential treatment option for Marfan-related aortic disease.