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Published on: November 20, 2017
Complement Cross Talks With H-K-ATPase to Upregulate Runx2 in Human Aortic Valve Interstitial Cells
Xin-Sheng Deng1, Xianzhong Meng2, David Fullerton2
1Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Insights
Complement interacts with H-K-ATPase to increase Runx2 in calcific aortic valve disease (CAVD) via ERK1/2 signaling. Targeting complement or H-K-ATPase may treat CAVD.
Area of Science:
- Cardiovascular Biology
- Cellular Pathophysiology
- Molecular Medicine
Background:
- Calcific aortic valve disease (CAVD) is a complex, progressive disorder.
- The complement system and H-K-ATPase are implicated in CAVD pathogenesis.
- Complement upregulates Runx2, promoting fibrosis in aortic valve interstitial cells (AVICs).
Purpose of the Study:
- To investigate the crosstalk between complement and H-K-ATPase in regulating Runx2 in human AVICs.
- To elucidate the role of ERK1/2 signaling in this interaction.
- To identify potential therapeutic targets for CAVD.
Main Methods:
- Human AVICs were isolated from normal and calcified valves.
- Cells were treated with complement, H-K-ATPase, or ERK1/2 inhibitors.
- Expression levels and signaling pathways were analyzed using RT-PCR, immunofluorescence, and Western blot.
Main Results:
- Calcified AVICs showed higher H-K-ATPase levels than normal AVICs.
- Complement treatment increased H-K-ATPase and Runx2 expression in AVICs, activating ERK1/2 signaling.
- Inhibiting H-K-ATPase or ERK1/2 blocked complement-induced Runx2 upregulation.
Conclusions:
- Complement and H-K-ATPase interact to upregulate Runx2 in human AVICs through ERK1/2 activation.
- H-K-ATPase plays a significant role in CAVD pathogenesis.
- Targeting the complement system or H-K-ATPase offers potential therapeutic strategies for CAVD.
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.
