Abstract
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.
Highlights
Calcific aortic valve disease (CAVD) is a life-threatening disorder affecting approximately 2% of people older than 65 years
Building upon a study showing an association between increased expression of CaV1.2 in the aortic valve and CAVD [19], our combination of valve interstitial cells (VICs) culture and in vivo models demonstrates that increased Ca2+ influx through CaV1.2 is, causal for the initiation of calcific lesions within the aortic valve
The role of CaV1.2 in this model, echoing the GWAS of patients with more advanced CAVD [19], is underlined by our experiments showing that blocking CaV1.2-channel activity with verapamil reduced the α-smooth muscle actin (α-SMA) signal of myofibroblast activation in cultured VICs and decreased the valve lesions in our in vivo model
Summary
Calcific aortic valve disease (CAVD) is a life-threatening disorder affecting approximately 2% of people older than 65 years. Dystrophic calcification results from myofibroblast differentiation of VICs in response to paracrine action of TGF-β. Activated myofibroblasts remodel the extracellular matrix that alters the local milieu in ways that promote calcification, such as by secretion of MMPs that release latent TGF-β within the extracellular matrix, thereby augmenting VIC differentiation to myofibroblasts. Activated myofibroblasts eventually undergo apoptosis and deposit calcium salts that precipitate calcification [4]. The ectopically transformed osteoblasts secrete bone matrix [5, 6], as reflected by upregulation of canonical osteogenic signaling pathways, such as the BMP pathway and the Wnt-signaling pathway, in diseased calcific aortic valves [6–8]. Chondrogenic signaling in diseased valves is marked by the expression of Aggrecan (ACAN) and SOX9, a major chondrogenic transcriptional regulator [9]
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