Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects.
Activation of AcvR1-Mediated Signaling Results in Semilunar Valve Defects.
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DOI：
10.3390/jcdd9080272
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发表时间：
2022-08-16
影响因子：
2.4
通讯作者：
中科院分区：
文献类型：
--
作者：
钙化性主动脉瓣疾病（CAVD）是一种常见的心脏缺陷，特别是在老年人群中。虽然在CAVD发病机制中已经确定了几个风险因素，如双叶瓣膜结构和老年，但导致这种情况的分子机制仍在积极研究中。通过激活素I型受体（AcvRI）的骨形态发生蛋白信号传导在涉及钙化的生理和病理过程中起重要作用，例如，骨形成和异位骨化。此外，AcvRI是正常心脏瓣膜发育所必需的，但其在主动脉瓣疾病中的作用（如果有的话）目前尚不清楚。在这里，我们诱导的表达组成型活性AcvRI在发育中的小鼠胚胎的内皮细胞和细胞在瓣膜小叶壁交界处，是不是内皮细胞来源的Nfac 1Cre转基因。突变小鼠出生时存活，但在出生后早期显示主动脉瓣和肺动脉瓣叶增厚。成年突变小鼠发生高频率的主动脉瓣狭窄，主动脉瓣硬化，并在小叶-壁连接处显示阿辛蓝阳性的肥大软骨细胞样细胞。仅在低外显率时观察到钙化。此外，我们观察到，与炎症相关的细胞因子信号传导，平滑肌细胞收缩，cGMP信号传导相关的基因集的表达水平在突变体中改变时，与对照组相比。这项工作表明，在小鼠模型中，Nfatc 1Cre重组结构域中的这种连续AcvRI活性导致主动脉瓣结构和功能的病理变化。
Calcific aortic valve disease (CAVD) is a common cardiac defect, particularly in the aging population. While several risk factors, such as bi-leaflet valve structure and old age, have been identified in CAVD pathogenesis, molecular mechanisms resulting in this condition are still under active investigation. Bone morphogenetic protein signaling via the activin type I receptor (AcvRI) plays an important role during physiological and pathological processes involving calcification, e.g., bone formation and heterotopic ossification. In addition, AcvRI is required for normal cardiac valve development, yet its role in aortic valve disease, if any, is currently unknown. Here, we induced the expression of constitutively active AcvRI in developing mouse embryos in the endocardium and in cells at the valve leaflet–wall junction that are not of endocardium origin using the Nfac1Cre transgene. The mutant mice were born alive, but showed thickened aortic and pulmonary valve leaflets during the early postnatal period. Adult mutant mice developed aortic stenosis with high frequency, sclerotic aortic valves, and displayed Alcian Blue-positive hypertrophic chondrocyte-like cells at the leaflet–wall junction. Calcification was only seen with low penetrance. In addition, we observed that the expression levels of gene sets associated with inflammation-related cytokine signaling, smooth muscle cell contraction, and cGMP signaling were altered in the mutants when compared with those of the controls. This work shows that, in a mouse model, such continuous AcvRI activity in the Nfatc1Cre recombination domain results in pathological changes in the aortic valve structure and function.
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影响因子：
20.1
作者：
Blaser, Mark C.;Wei, Kuiru;Simmons, Craig A.
通讯作者：
Simmons, Craig A.
影响因子：
64.8
作者：
Garg, V;Muth, AN;Srivastava, D
通讯作者：
Srivastava, D
影响因子：
17.1
作者：
Hatsell SJ;Idone V;Wolken DM;Huang L;Kim HJ;Wang L;Wen X;Nannuru KC;Jimenez J;Xie L;Das N;Makhoul G;Chernomorsky R;D'Ambrosio D;Corpina RA;Schoenherr CJ;Feeley K;Yu PB;Yancopoulos GD;Murphy AJ;Economides AN
通讯作者：
Economides AN
影响因子：
18.2
作者：
Hinton RB;Yutzey KE
通讯作者：
Yutzey KE
影响因子：
5.2
作者：
Joziasse, Irene C.;Smith, Kelly A.;Bakkers, Jeroen
通讯作者：
Bakkers, Jeroen