Deletion of AT1a (Angiotensin II Type 1a) Receptor or Inhibition of Angiotensinogen Synthesis Attenuates Thoracic Aortopathies in Fibrillin1(C1041G/+) Mice.
Deletion of AT1a (Angiotensin II Type 1a) Receptor or Inhibition of Angiotensinogen Synthesis Attenuates Thoracic Aortopathies in Fibrillin1(C1041G/+) Mice.
复制标题
DOI：
10.1161/atvbaha.121.315715
复制
发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Daugherty A
中科院分区：
文献类型：
--
作者：
Chen JZ;Sawada H;Ye D;Katsumata Y;Kukida M;Ohno-Urabe S;Moorleghen JJ;Franklin MK;Howatt DA;Sheppard MB;Mullick AE;Lu HS;Daugherty A
马凡氏综合征的一个主要特征是胸主动脉瘤（TAA）。肾素血管紧张素系统通过血管紧张素II（AngII）受体1a型（AT 1aR）对TAA进展的作用仍存在争议，因为血管紧张素受体阻滞剂的有益作用归因于脱靶效应。本研究采用遗传学和药理学模式分别减弱血管紧张素受体和配体，以确定其对TAA的作用，在小鼠与Fbn 1C 1041 G/+单倍不足。发现Fbn 1C 1041 G/+小鼠的TAA具有显著的性二态性。雄性在12个月内显示主动脉扩张，而Fbn 1C 1041 G/+雌性的主动脉扩张与野生型小鼠无显著差异。为了确定AT 1aR的作用，产生了AT 1aR为+/+或-/-的Fbn 1C 1041 G/+小鼠。AT 1aR缺失减少了1至12月龄男性升主动脉和主动脉根直径的扩张。中膜增厚和弹性蛋白断裂减弱。对雄性Fbn 1C 1041 G/+小鼠施用针对血管紧张素原的反义寡核苷酸（AGT-ASO）以确定AngII消耗的影响。AGT-ASO给药减弱了升主动脉和主动脉根的扩张，并减少了细胞外重塑。主动脉转录组分析确定了抑制肾素血管紧张素系统减少Fbn 1C 1041 G/+小鼠主动脉扩张的潜在靶点。删除AT 1aR或抑制AngII的产生在减轻雄性Fbn 1C 1041 G/+小鼠近端胸主动脉的病理学方面具有相似的作用。肾素血管紧张素系统的抑制减弱了与Fbn 1C 1041 G/+小鼠病理学相关的主动脉内基因的失调。
A cardinal feature of Marfan syndrome is thoracic aortic aneurysm (TAA). The contribution of the renin angiotensin system via angiotensin II (AngII) receptor type 1a (AT1aR) to TAA progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacologic modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on TAA in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+). TAA in Fbn1C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1C1041G/+ females did not differ significantly from wild type mice. To determine the role of AT1aR, Fbn1C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen (AGT-ASO) was administered to male Fbn1C1041G/+ mice to determine the effects of AngII depletion. AGT-ASO administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin angiotensin system reduced aortic dilation in Fbn1C1041G/+ mice. Deletion of AT1aR or inhibition of AngII production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1C1041G/+ mice. Inhibition of the renin angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1C1041G/+ mice.