Calcific aortic valve disease (CAVD) is a slowly progressive fibro-calcific valve leaflet disorder. The underlying pathophysiology is complex and not yet well understood. Complement is known to play a role in the pathogenesis of CAVD by upregulating Runx2 to induce profibrogenic change in human aortic valve interstitial cells (AVICs). Furthermore, H-K-ATPase has independently been shown to induce tissue calcification. Therefore, we hypothesized that complement cross talks with H-K-ATPase to upregulate Runx2 in human AVICs.
Materials and methods
Human AVICs were isolated from normal and calcified aortic valves. Cells were treated with a variation of complement, H-K-ATPase, or ERK1/2 inhibitors. H-K-ATPase and its association with complement in AVICs were investigated by reverse transcriptase–polymerase chain reaction, immunofluorescence, and Western blot.
Calcified human AVICs expressed significantly higher H-K-ATPase level than normal human AVICs. Presence of complement C3 with H-K-ATPase is found in AVICs after complement treatment. Complement induced both H-K-ATPase and Runx2 expression in AVICs, which was associated with increased phosphorylation of ERK1/2 and its downstream molecule p-70 S6. Pharmacological inhibition of either H-K-ATPase or Erk1/2 abolished complement-induced Runx2 expression.
These findings indicate that complement cross talks with H-K-ATPase to upregulate Runx2 in human AVICs by activation of ERK1/2 signaling pathways. The study revealed the potential role of H-K-ATPase in the pathogenesis of CAVD and therapeutically targeting either complement system or H-K-ATPase may limit the development of CAVD.
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Published online: February 21, 2023
Accepted: December 25, 2022
Received in revised form: November 16, 2022
Received: June 15, 2022
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