Targeting Tyrosine Hydroxylase for Abdominal Aortic Aneurysm Impact on Inflammation, Oxidative Stress, and Vascular Remodeling
Targeting Tyrosine Hydroxylase for Abdominal Aortic Aneurysm Impact on Inflammation, Oxidative Stress, and Vascular Remodeling
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DOI：
10.1161/hypertensionaha.121.17517
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发表时间：
2021-09-01
期刊：
影响因子：
8.3
通讯作者：
Martinez-Gonzalez, Jose
中科院分区：
文献类型：
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作者：
Canes, Laia;Alonso, Judith;Martinez-Gonzalez, Jose
预防腹主动脉瘤（AAA）破裂或减缓动脉瘤进展的药物治疗仍然是一个挑战。越来越多的人认识到交感神经活动可能在AAA的发病机制中发挥作用;然而，该途径的影响仍不清楚。在这里，我们发现，酪氨酸羟化酶（TH）、多巴胺β-羟化酶（DBH）和去甲肾上腺素转运蛋白SLC 6A 2的表达在腹主动脉瘤患者的腹主动脉样本和2种对血管紧张素II敏感的动物模型的动脉瘤中上调。（血管紧张素II）诱导的AAA：载脂蛋白E缺乏（ApoE（-/-））模型和过表达人核受体NOR-1的转基因小鼠（神经元衍生的孤儿受体-1）（TgNOR-1（VSMC））。TH定位于支配局部血管系统的交感神经，但也定位于炎症细胞，以及人和小鼠AAA中分散的血管平滑肌细胞。有趣的是，强力霉素对血管紧张素II治疗的TgNOR-1（VSMC）小鼠AAA形成的预防作用与血管Th表达的正常化有关。此外，TH特异性抑制剂α-甲基-p-酪氨酸保护血管紧张素II诱导的AAA形成，限制主动脉直径的逐步增加，而不影响血压。药物使MMP 2（基质金属蛋白酶2）表达和MMP活性正常化，保持弹性蛋白的完整性，减弱血管紧张素II介导的血管氧化应激和炎症标志物的升高，并减少炎症浸润。最后，NOR-1，其表达与TH在人AAA中的表达相关，能够在瞬时转染测定中驱动人TH转录活性。因此，TH通路的上调在AAA的病理生理学中可能是至关重要的，支持靶向TH用于AAA管理的药理学策略的潜力。
Pharmacological treatments for preventing abdominal aortic aneurysm (AAA) rupture or slowing aneurysm progression remain a challenge. It is increasingly recognized that sympathetic activity might play a role in the pathogenesis of AAA; however, the impact of this pathway remains unclear. Here, we show that the expression of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and the norepinephrine transporter SLC6A2 is upregulated in abdominal aorta samples from AAA patients and in the aneurysmal aorta from 2 animal models susceptible to Ang II (angiotensin II)-induced AAA: the apolipoprotein E-deficient (ApoE(-/-)) model and a transgenic mouse that overexpresses the human nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in the vascular wall (TgNOR-1(VSMC)). TH localizes to sympathetic nerves innervating the local vasculature, but also to inflammatory cells, and scattered vascular smooth muscle cell in human and mouse AAA. Interestingly, the preventive effect of doxycycline on AAA formation in Ang II-treated TgNOR-1(VSMC) mice was associated to the normalization of vascular Th expression. Moreover, the TH specific inhibitor alpha-methyl-p-tyrosine protected against Ang II-induced AAA formation, limiting the progressive increase in aortic diameter without affecting blood pressure. The drug normalized MMP2 (matrix metalloproteinase 2) expression and MMP activity, preserving elastin integrity, attenuated the Ang II-mediated rise in vascular oxidative stress and inflammatory markers and reduced the inflammatory infiltrate. Finally, NOR-1, whose expression correlated with that of TH in human AAA, was able to drive human TH transcriptional activity in transient transfection assays. Therefore, the upregulation of the TH pathway could be critical in the pathophysiology of AAA, supporting the potential of pharmacological strategies targeting TH for AAA management.