High mobility group box 1 induces calcification of aortic valve interstitial cells via toll-like receptor 4

Area of Science:

• Cardiovascular Biology
• Inflammation Research
• Cellular Pathophysiology

Background:

• Calcific aortic valve disease (CAVD) involves chronic inflammation and aortic valve interstitial cell (AVIC) calcification.
• The precise molecular mechanisms underlying CAVD pathogenesis require further elucidation.

Purpose of the Study:

• To investigate the role of high mobility group box 1 (HMGB1) signaling through toll-like receptor 4 (TLR4) in regulating inflammation and calcification within AVICs.
• To explore the therapeutic potential of targeting the HMGB1-TLR4 axis in CAVD.

Main Methods:

• Quantification of HMGB1 and TLR4 expression in human CAVD aortic valves.
• In vitro studies using cultured primary AVICs from wild-type and TLR4 knockout mice.
• Assessment of mineralization, osteogenic gene expression, and inflammatory signaling pathways (p38, NF-κB) following HMGB1 stimulation and TLR4 inhibition.

Main Results:

• Elevated HMGB1 and TLR4 expression observed in calcified human aortic valves.
• HMGB1 treatment increased AVIC mineralization and osteogenic gene expression in a dose-dependent manner.
• These HMGB1-induced effects were significantly attenuated in TLR4-deficient AVICs and upon treatment with TLR4-specific antibodies.
• HMGB1 modulated p38 and nuclear factor-κB (NF-κB) activation, with TLR4 mediating these signaling events.

Conclusions:

• Toll-like receptor 4 (TLR4) acts as a critical mediator in high mobility group box 1 (HMGB1)-induced calcification of aortic valve interstitial cells (AVICs).
• The HMGB1-TLR4 pathway influences the activation of p38 and nuclear factor-κB (NF-κB), contributing to CAVD pathogenesis.
• Targeting the TLR4 receptor presents a potential therapeutic strategy for managing calcific aortic valve disease.