Increased Ca2+ influx through CaV1.2 drives aortic valve calcification.
Increased Ca2+ influx through CaV1.2 drives aortic valve calcification.
复制标题
通过CaV1.2增加的Ca2+内流驱动主动脉瓣钙化。
DOI：
10.1172/jci.insight.155569
复制
发表时间：
2022-03-08
期刊：
影响因子：
8
通讯作者：
Pitt GS
中科院分区：
文献类型：
--
作者：
Matsui M;Bouchareb R;Storto M;Hussain Y;Gregg A;Marx SO;Pitt GS
钙化性主动脉瓣疾病（CAVD）是遗传性的，最近的GWAS显示。虽然与CACNA1C（编码CaV1.2 L型电压门控Ca2+通道）表达增加和Ca2+信号增加相关的多态性与CAVD相关，但通过可药用CaV1.2增加的Ca2+内流是否会导致CAVD尚不清楚。我们证实了手术切除的患者主动脉瓣中CaV1.2表达增加与CAVD之间的相关性。我们用转基因小鼠模型扩展了我们的研究，该模型模拟了主动脉瓣间质细胞（VIC）内CaV1.2表达的增加。在保持正常饮食的年轻小鼠中，我们观察到营养不良性瓣膜病变，其模拟症状前CAVD中发现的变化，并显示这些瓣膜病变内软骨形成和成骨转录调节因子的激活。维拉帕米是一种临床上使用的CaV1.2拮抗剂，长期给药可减缓体内病变发展的进展。利用维克培养物，我们证明了通过CaV1.2增加的Ca 2+内流驱动信号程序，导致VIC的肌成纤维细胞活化和与主动脉瓣钙化相关的基因上调。我们的数据支持Ca2+通过CaV1.2内流在CAVD中的因果作用，并表明早期使用Ca2+通道阻滞剂治疗是一种有效的治疗策略。
Calcific aortic valve disease (CAVD) is heritable, as revealed by recent GWAS. While polymorphisms linked to increased expression of CACNA1C — encoding the CaV1.2 L-type voltage-gated Ca2+ channel — and increased Ca2+ signaling are associated with CAVD, whether increased Ca2+ influx through the druggable CaV1.2 causes CAVD is unknown. We confirmed the association between increased CaV1.2 expression and CAVD in surgically removed aortic valves from patients. We extended our studies with a transgenic mouse model that mimics increased CaV1.2 expression within aortic valve interstitial cells (VICs). In young mice maintained on normal chow, we observed dystrophic valve lesions that mimic changes found in presymptomatic CAVD and showed activation of chondrogenic and osteogenic transcriptional regulators within these valve lesions. Chronic administration of verapamil, a CaV1.2 antagonist used clinically, slowed the progression of lesion development in vivo. Exploiting VIC cultures, we demonstrated that increased Ca2+ influx through CaV1.2 drives signaling programs that lead to myofibroblast activation of VICs and upregulation of genes associated with aortic valve calcification. Our data support a causal role for Ca2+ influx through CaV1.2 in CAVD and suggest that early treatment with Ca2+ channel blockers is an effective therapeutic strategy.
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DOI：
10.1161/circgenetics.115.001145
发表时间：
2015-12
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Guauque-Olarte S;Messika-Zeitoun D;Droit A;Lamontagne M;Tremblay-Marchand J;Lavoie-Charland E;Gaudreault N;Arsenault BJ;Dubé MP;Tardif JC;Body SC;Seidman JG;Boileau C;Mathieu P;Pibarot P;Bossé Y
通讯作者：
Bossé Y
影响因子：
3
作者：
Baum J;Duffy HS
通讯作者：
Duffy HS
DOI：
10.1073/pnas.1908981116
发表时间：
2019-10-22
影响因子：
11.1
作者：
Atsuta, Yuji;Tomizawa, Reiko R.;Tabin, Clifford J.
通讯作者：
Tabin, Clifford J.
影响因子：
4.6
作者：
Guauque-Olarte, Sandra;Droit, Arnaud;Bosse, Yohan
通讯作者：
Bosse, Yohan
影响因子：
158.5
作者：
Cowell, SJ;Newby, DE;Boon, NA
通讯作者：
Boon, NA