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ORIGINAL RESEARCH article

Front. Cardiovasc. Med.
Sec. Heart Valve Disease
Volume 11 - 2024 | doi: 10.3389/fcvm.2024.1410862

Cathepsin D Elevates the Fibrocalcific Activity in Human Aortic Valve Cells through the ERK1/2-Sox9 Pathway

Provisionally accepted
Xianzhong Meng Xianzhong Meng *Qingzhou Yao Qingzhou Yao Erlinda The Erlinda The Balachandar Nedumaran Balachandar Nedumaran Yufeng Zhai Yufeng Zhai Lihua Ao Lihua Ao David A. Fullerton David A. Fullerton
  • University of Colorado, Denver, Colorado, United States

The final, formatted version of the article will be published soon.

    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 runtrelated 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 upregulates cathepsin D to elevate AVIC fibrocalcific activity. Over-expression of cathepsin D in the aortic valve may enhance the pathobiological activities in AVICs.

    Keywords: Cathepsin D, Matrilin 2, Sox9, Fibrocalcification, CAVD Conceptualization, X.M, Methodology, Y.Q., B.N., E.T. and L.A., Investigation, Y.Q., E.T., L.A. and YZ., Data Acquisition and Analysis, Y.Q., Writing -Original Draft Preparation, Y.Q., Writing -Review & Editing, X.M. and D.A.F., Supervision, X.M., Project Administration, X.M.

    Received: 01 Apr 2024; Accepted: 05 Sep 2024.

    Copyright: © 2024 Meng, Yao, The, Nedumaran, Zhai, Ao and Fullerton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Xianzhong Meng, University of Colorado, Denver, CO 80203, Colorado, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.