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

Abstract

Aims Calcific aortic valve disease (CAVD) 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 CAVD is yet to be elucidated. The present study sought to determine the potential role of zinc in the pathogenesis of CAVD. Methods and results Using a combination of a human valve interstitial cell (hVIC) calcification model, human aortic valve tissues, and blood samples, we report that 20 μM zinc supplementation attenuates 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 signalling 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 CAVD. Moreover, we reveal that 20 μM zinc treatment prevents the reduction of GPR39 observed in calcified hVICs. 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 CAVD, 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 CAVD.

The year in cardiovascular medicine 2020: valvular heart disease

“… 20 Zinc transporter molecules have been proven as regulators of valvular interstitial cell calcification in vitro. 21 This finding, combined with the identification of a significant reduction in serum levels of zinc in patients with calcific AS, suggests a role of zinc metabolism in early valve degeneration. 21 Acquired somatic mutations in haematopoietic precursors is increasingly being reported in several chronic conditions.…”

“… 21 This finding, combined with the identification of a significant reduction in serum levels of zinc in patients with calcific AS, suggests a role of zinc metabolism in early valve degeneration. 21 Acquired somatic mutations in haematopoietic precursors is increasingly being reported in several chronic conditions. Patients with AS show an age-related prevalence of acquired somatic mutations in haematopoietic lineages related with pro-inflammatory leucocyte subsets, up to a prevalence of nearly 53% in >90-year-old TAVI candidates.…”

The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target

“…Zinc was first indicated to activate GPR39 in 2004 [ 8 ], and in 2007 two research groups showed that GPR39 senses changes in extracellular zinc concentrations, which results in intracellular signaling pathway activation [ 6 , 7 ]; although the existence of a Zn 2+ -sensing receptor was already suggested in 2001 by functional identification [ 5 ]. Zn 2+ is found in all tissues in relatively high concentrations [ 9 ] and has been so far shown to activate GPR39 in bones, neurons, pancreatic cells, salivary gland cells, epithelial cells of the colon (colonocytes), epidermal cells of the skin (keratinocytes), skin fibroblasts, endothelial cells, cardiac valve interstitial cells, aortic vascular smooth muscle cells and prostate cancer cells [ 14 , 24 , 26 , 36 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Extracellular Zn 2+ , able to activate GPR39, can be released from the pancreatic β-cells together with insulin, nerve synapses together with glutamate, salivary gland vesicles, Paneth cells of the intestinal crypts or in connection with cell injury and death [ 14 , 15 , 16 , 51 , 52 ].…”

“…Another study used human valve interstitial cells to demonstrate that Zn 2+ -induced GPR39 activation inhibited apoptosis and osteogenic differentiation via ERK1/2, attenuating calcification and therefore indicating protection against calcific aortic valve disease. Serum Zn 2+ and GPR39 expression levels were reduced in calcified human aortic valve patients, but treatment with 20 µM Zn 2+ prevented the reduction, and ZIP13 and ZIP14 deficiencies inhibited the calcification [ 44 ]. Testing the potential of GPR39 agonists to inhibit calcification was not studied here but would be of importance.…”

“…These effects were shown to be mediated by the NF-κB pathway [ 32 ]. These studies bring novel insight into the role of GPR39 in the cardiovascular system and notably, indicate further possibilities to investigate GPR39 as a therapeutic target in heart and vascular diseases [ 32 , 44 , 49 , 50 ]. Importantly, the latter study further indicates the connection of GPR39 signaling to inflammation and to the NF-κB pathway activation, as also observed in connection with osteoarthritis and rheumatoid arthritis [ 30 , 31 , 32 ].…”