Abstract 19365: A Gain-of-Function Mutation in CaV1.2 (Cacna1c) Promotes Progressive Aortic Valve Stenosis in Mouse
Introduction: Calcific aortic valve stenosis (CAVS) is a life threatening disorder affecting approximately 2% of people > 65 yeas. Genome-wide association studies recently identified CACNA1C, encoding the alpha subunit of voltage dependent L-type calcium channel CaV1.2 as a new CAVS susceptibility gene and expression quantitative trait loci (eQTL) mapping suggested that increased Ca2+ influx through the channel drove the phenotype. Beyond this genetic association, little is known about roles for CaV1.2 in the aortic valve and how increased Ca2+ influx through CaV1.2 contributes to CAVS.
Hypothesis: We hypothesized that Cacna1c is expressed in the valve; and gain-of-function mutations in Cacna1c that increase Ca2+ influx promote CAVS through activation of Ca2+-dependent downstream signaling pathways. Further, we hypothesize that activation of these signaling pathways transforms valve cells from a fibroblast-like phenotype to a chondrocyte-like phenotype that supports calcification.
Methods: We exploited a Cacna1c reporter line to define expression patterns in valves. 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 valve interstitial cells (VICs) with a Cre recombinase driven by the transcription factor Scleraxis (Scx). For both mouse models, we evaluated valves by histology to assess CAVS and examined transcriptional responses by qPCR.
Results and Conclusions: Cacna1c is expressed primarily in the annulus of adult aortic valves. The G406R knockin mouse model displayed chondrocyte-like transformation of cells in the attachment of the cusps to the annulus. These areas were markedly thickened compared to wild type litter mate controls and showed evidence of accelerated calcification. Ectopic activation of the G406R mutant transgene in VICs by Scx-Cre resulted in marked thickening of the valve cusps. Our results indicate that increased Ca2+ influx through CaV1.2 in the aortic valve leads to thickened valves and calcification. Ectopic expression of the mutant CaV1.2 in valve cells demonstrates that the role of CaV1.2 is cell autonomous for the development of CAVs.
Author Disclosures: M. Matsui: None. K. Kadakia: None. E. Wei: None. D. Sinden: None. G. Pitt: None.
- © 2016 by American Heart Association, Inc.