The Heart Valve Society

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A Gain-of-Function Mutation in CaV1.2 (Cacna1c) Promotes Progressive Aortic Valve Stenosis in Mouse
Maiko Matsui, Mara Storto, Yasin Hussain, Daniel Sinden, Geoffrey S. Pitt.
Weill Cornell Medicine, New York, NY, USA.

OBJECTIVE: A genome-wide association study identified CACNA1C, encoding the alpha subunit of voltage dependent L-type calcium channel CaV1.2, as a new aortic valve stenosis (AVS) susceptibility gene. Beyond this genetic association, little is known about how increased Ca2+ influx through CaV1.2 contributes to AVS. We hypothesized that Cacna1c is expressed in the valve; and gain-of-function mutations in Cacna1c that increase Ca2+ influx promote AVS through activation of Ca2+-dependent downstream signaling pathways resulting in transformation of valve cells to a chondro/osteo-progenitor-like phenotype that supports development of AVS. METHODS: We generated two mouse lines: a G406R knockin mutation in Cacna1c, which decreases channel inactivation and leads to Ca2+ influx; and we activated a G406R mutant Cacna1c transgene specifically in AoV with a Cre recombinase driven by the transcription factor Scleraxis (Scx). Porcine AoV interstitial cells (VICs) culture was used to study underlying cellular mechanisms of AVS caused by excess influx of Ca2+ through CaV1.2. Further, we tested if calcium channel blockade (CCB) delivered through an implanted mini-osmotic pump can ameliorate chondrocyte-like cell phenotype. RESULTS: G406R knockin mice displayed chondrocyte-like transformation of cells in the annulus. Ectopic over expression of the G406R mutant transgene in AoV by Scx-Cre drove the appearance of chondro/osteo-progenitor-like cells in the annulus, and at much earlier stage (4 months old). Overexpressing CaV1.2 in porcine aortic VIC culture resulted in increased calcific nodule formation. Further, in vivo CCB delivery led to reduced chondro/osteo-progenitor-like cell formation. CONCLUSIONS: Our results indicate that increased Ca2+ influx through CaV1.2 in the AoV leads to chondro/osteo-progenitor-like phenotype. Ectopic expression of the mutant CaV1.2 in AoV demonstrates that the role of CaV1.2 is tissue autonomous for the development of AVS. Further, our results suggest that CCBs may be candidates to slow or even prevent the progression of AVS.


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