1. Academic Validation
  2. Complement Cross Talks With H-K-ATPase to Upregulate Runx2 in Human Aortic Valve Interstitial Cells

Complement Cross Talks With H-K-ATPase to Upregulate Runx2 in Human Aortic Valve Interstitial Cells

  • J Surg Res. 2023 Feb 21;286:118-126. doi: 10.1016/j.jss.2022.12.028.
Xin-Sheng Deng 1 Xianzhong Meng 2 David Fullerton 2 Matthew Stone 2 John Iguidbashian 2 James Jaggers 3
Affiliations

Affiliations

  • 1 Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 2 Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 3 Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: James.Jaggers@childrenscolorado.org.
Abstract

Introduction: 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.

Results: 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.

Conclusions: 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.

Keywords

Aortic valve; Complement; Cross talk; H-K-ATPase; Runx2.

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