Increased Ca2+ influx through CaV1.2 drives aortic valve calcification.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genetics

Background:

• Calcific aortic valve disease (CAVD) has a heritable component, with genetic links to CACNA1C, which encodes the CaV1.2 calcium channel.
• The precise role of Ca2+ influx via CaV1.2 in CAVD pathogenesis remains unclear.

Purpose of the Study:

• To investigate the causal role of Ca2+ influx through the CaV1.2 channel in the development of CAVD.
• To evaluate the therapeutic potential of CaV1.2 antagonists in preclinical models of CAVD.

Main Methods:

• Confirmed increased CaV1.2 expression in human CAVD patient samples.
• Utilized a transgenic mouse model with elevated CaV1.2 expression in valve interstitial cells (VICs).
• Administered verapamil (a CaV1.2 antagonist) to mice and analyzed VICs in vitro.

Main Results:

• Transgenic mice exhibited dystrophic valve lesions and activated chondrogenic/osteogenic pathways, mimicking early CAVD.
• Verapamil treatment significantly slowed lesion progression in vivo.
• In vitro studies showed Ca2+ influx via CaV1.2 promotes VIC myofibroblast activation and calcification-related gene expression.

Conclusions:

• Ca2+ influx through CaV1.2 plays a causal role in CAVD.
• Targeting CaV1.2 with channel blockers represents a promising early therapeutic strategy for CAVD.