Complement Upregulates Runx-2 to Induce Profibrogenic Change in Aortic Valve Interstitial Cells

Area of Science:

• Cardiovascular Biology
• Immunology
• Cellular Biology

Background:

• Calcific aortic valve disease (CAVD) involves calcium deposition and fibrosis.
• Active complement components are present in human stenotic aortic valves.
• Runt-related transcription factor 2 (Runx-2) is implicated in tissue calcification.

Purpose of the Study:

• To investigate if complement upregulates Runx-2 in human aortic valve interstitial cells (AVICs).
• To determine if this upregulation induces profibrogenic changes in AVICs.

Main Methods:

• AVICs were isolated from normal and CAVD donor valves.
• Cells were treated with complement cocktails, and profibrogenic activities were analyzed.
• Western blot assays and collagen staining were used to assess signaling molecules and collagen deposition.

Main Results:

• Complement exposure dose- and time-dependently increased profibrogenic activities and collagen deposition in AVICs.
• This response was linked to increased Runx-2 expression and ERK1/2 phosphorylation.
• Runx-2 silencing and ERK1/2 inhibition reduced collagen and MMP-9 levels, while heat-inactivated complement had less effect.

Conclusions:

• Complement induces profibrogenic activities in AVICs via ERK1/2-mediated Runx-2 signaling.
• This study identifies a potential role for complement in CAVD pathogenesis.
• Targeting complement-mediated pathways may offer a therapeutic strategy for CAVD.