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Updated: Jun 23, 2026
Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification
Published on: November 20, 2017
Cathepsin D elevates the fibrocalcific activity in human aortic valve cells through the ERK1/2-Sox9 pathway
Qingzhou Yao1, Erlinda The1, Balachandar Nedumaran1
1Department of Surgery, University of Colorado, Denver, CO, United States.
Background:
Human Aortic valve interstitial cells (AVICs) from calcific aortic valve disease (CAVD)-affected valves exhibit elevated fibrocalcific activity although the underlying mechanism remains incompletely understood. This study aimed to identify endogenous factors that promote aortic valve fibrocalcification.
Methods And Results:
Proteomic analysis found increased cathepsin D levels in AVICs from CAVD-affected valves compared to AVICs from normal valves, and this finding was validated by immunoblotting. ELISA assay identified exacerbated release of cathepsin D by AVICs of diseased valves. Recombinant human cathepsin D upregulated the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), collagen I and collagen IV in human AVICs, resulting in the deposition of calcium and collagen. Blocking of the ERK1/2-Sox9 signaling pathway markedly reduced the pro-fibrocalcific effect of cathepsin D. Moreover, normal AVICs express and release greater levels of cathepsin D when exposed to soluble matrilin 2. Knockdown of cathepsin D attenuated the fibrocalcific response induced by soluble matrilin 2.
Conclusion:
AVICs of diseased aortic valves produce and release greater levels of cathepsin D that exerts a pro-fibrocalcific effect on AVICs through the ERK1/2-Sox9 pathway. Soluble matrilin 2 up-regulates cathepsin D to elevate AVIC fibrocalcific activity. Over-expression of cathepsin D in the aortic valve may enhance the pathobiological activities in AVICs.
