Zinc ameliorates human aortic valve calcification through GPR39 mediated ERK1/2 signaling pathway

AIMS: Calcific aortic valve disease is the most common heart valve disease in the Western world. It has been reported that zinc is accumulated in calcified human aortic valves. However, whether zinc directly regulates calcific aortic valve disease is yet to be elucidated. The present study sought to determine the potential role of zinc in the pathogenesis of calcific aortic valve disease.

METHODS AND RESULTS: Using a combination of a human valve interstitial cell calcification model, human aortic valve tissues and blood samples, we report that 20 μM zinc supplementation attenuates human valve interstitial cell (hVIC) in vitro calcification, and that this is mediated through inhibition of apoptosis and osteogenic differentiation via the zinc sensing receptor GPR39-dependent ERK1/2 signaling pathway. Furthermore, we report that GPR39 protein expression is dramatically reduced in calcified human aortic valves, and there is a significant reduction in zinc serum levels in patients with calcific aortic valve disease. Moreover, we reveal that 20 μM zinc treatment prevents the reduction of GPR39 observed in calcified human valve interstitial cells. We also show that the zinc transporter ZIP13 and ZIP14 are significantly increased in hVICs in response to zinc treatment. Knockdown of ZIP13 or ZIP14 significantly inhibited hVIC in vitro calcification and osteogenic differentiation.

CONCLUSIONS: Together, these findings suggest that zinc is a novel inhibitor of calcific aortic valve disease, and report that zinc transporter ZIP13 and ZIP14 are important regulators of hVIC in vitro calcification and osteogenic differentiation. Zinc supplementation may offer a potential therapeutic strategy for calcific aortic valve disease.

TRANSLATIONAL PERSPECTIVE: This study reports that the zinc sensing receptor GPR39 expression is decreased in calcified human aortic valve tissues and there is a significant reduction in zinc serum levels in patients with calcific aortic valve disease. Zinc treatment attenuates hVIC in vitro calcification through inhibition of apoptosis and osteogenic differentiation via GPR39-dependent ERK1/2 signaling pathway. Zinc transporter ZIP13 and ZIP14 are important regulators of hVIC in vitro calcification and osteogenic differentiation. Zinc supplementation is a potential therapeutic strategy for calcific aortic valve disease.