# Investigating the role of CaV1.2 in aortic valve stenosis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $798,364

## Abstract

Calcific aortic valve disease (CAVD) is a progressive life-threatening disorder characterized by dystrophic and/or
osteogenic transformation of valve cells (VICs), both leading to calcification. There are no medical therapies to
prevent or delay CAVD. Building on a recent meta-analysis of genome-wide association studies that
unexpectedly identified CACNA1C, encoding the pore-forming α subunit of the voltage gated L-type calcium
channel CaV1.2, as a candidate CAVD susceptibility gene, we present preliminary data suggesting that Ca2+
influx through CaV1.2 in VICs is causal for CAVD. This raises the tantalizing possibility that clinically used Ca2+
channel antagonists (CCBs) may be an effective therapy. Although CCBs are generally contraindicated in
patients with severe CAVD, they would be reasonable therapies earlier in the disease process. We propose to
test the overall hypotheses that: 1) increased Ca2+ influx through CaV1.2 in VICs leads to dystrophic and/or
osteogenic transformation; and 2) reduction of Ca2+ influx through CaV1.2 with CCBs and/or by targeting Ca2+-
dependent signaling molecules downstream of CaV1.2 in VICs delays CAVD progression. We developed novel
mouse models and innovative VIC cultures to test those overall hypotheses with the following Aims: Aim 1: Can
elevated Ca2+ influx through CaV1.2 activate VICs and/or increase expression of signaling pathway genes leading
to dystrophic or osteogenic calcification in the AoV? Using porcine and murine VICs enhanced by transfection
of informative cDNAs, we have developed means to dissect the Ca2+-dependent signaling pathways downstream
of CaV1.2 that contribute to CAVD, and thereby to discover new potential therapeutic targets. We propose a
multi-pronged approach to identify the critical downstream Ca2+-dependent signaling molecules and pathways
leading to activation of dystrophic VICs and/or osteogenic transformation of VICs; Aim 2: Can inhibition of CaV1.2
signaling pathways in the aortic valve decrease the valve pathology? With novel mouse models that mimic the
increased CaV1.2 expression and signaling in human CAVD, we propose to test if CCBs ameliorate valve lesions
and reverse the disease process once calcification is initiated. We further propose to build upon our identification
of novel candidate targets from Aim 1 to test if manipulating these targets similarly reduces or slows CAVD
progression. Aim 3: Does excess Ca2+ influx through CaV1.2 contribute to CAVD in the context of hyperlipidemia?
Hyperlipidemia is a prominent CAVD risk factor. In coronary artery disease, a related disorder, long ignored data
point to a synergistic interaction between CaV1.2 and hyperlipidemia. We propose: to test with novel mouse
models whether Ca2+ influx through CaV1.2 in VICs or macrophages accelerates AoV lesions in the context of
hyperlipidemia and, as a corollary, whether CCBs are effective when the disease process is driven by
hyperlipidemia, thereby determining whether targeting the CaV1.2...

## Key facts

- **NIH application ID:** 9998533
- **Project number:** 1R01HL151190-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Geoffrey S Pitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $798,364
- **Award type:** 1
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998533

## Citation

> US National Institutes of Health, RePORTER application 9998533, Investigating the role of CaV1.2 in aortic valve stenosis (1R01HL151190-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9998533. Licensed CC0.

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