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血管型埃勒斯-当洛斯综合征小鼠模型中预防主动脉破裂的治疗策略比较。

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome.

机构信息

Université de Paris, INSERM, U970, Paris Cardiovascular Research Centre, Paris, France.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique et Centre de Référence des Maladies Vasculaires Rares, Paris, France.

出版信息

PLoS Genet. 2022 Mar 4;18(3):e1010059. doi: 10.1371/journal.pgen.1010059. eCollection 2022 Mar.

DOI:10.1371/journal.pgen.1010059
PMID:35245290
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8926273/
Abstract

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.

摘要

血管型埃勒斯-当洛斯综合征是一种罕见的遗传性疾病，由 III 型胶原蛋白的基因突变引起。其预后尤其受到不可预测的动脉破裂的影响，目前尚无治疗共识。我们创建了一个 Col3a1+/G182R 敲入小鼠模型，并进行了全面的遗传、分子和生化特征分析。还测试了几种治疗策略。Col3a1+/G182R 小鼠表现出自发性死亡率，由胸主动脉破裂引起，这种死亡率类似于血管型埃勒斯-当洛斯综合征，雄性的存活率较低，非炎症性薄动脉和动脉胶原改变。主动脉的转录组分析显示与炎症和细胞应激反应相关的基因上调。与水相比，Col3a1+/G182R 小鼠的存活率不受β受体阻滞剂（普萘洛尔或塞利洛尔）的影响。另外两种血管扩张降压药（肼屈嗪、氨氯地平）对主动脉破裂和死亡率的影响相反。氯沙坦有显著的有益效果，停药后效果逆转，外源性血管紧张素 II 有明显的有害效果。这些结果表明，血管型埃勒斯-当洛斯综合征患者的肾素-血管紧张素系统阻断剂应作为一线药物治疗进行测试。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/eee026d4c002/pgen.1010059.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/ee1741568a7a/pgen.1010059.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/b2fa5bde485d/pgen.1010059.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/2bd75852b67d/pgen.1010059.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/eee026d4c002/pgen.1010059.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/ee1741568a7a/pgen.1010059.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/0384dafa1477/pgen.1010059.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/5ab769859a42/pgen.1010059.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/15dd0139ba17/pgen.1010059.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/cfc22ad7d8d3/pgen.1010059.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a42/8926273/1ee8dc27d0ab/pgen.1010059.g006.jpg
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