2. Academic Validation
  3. mTOR inhibition prevents coronary artery remodeling in a murine model of Kawasaki disease

mTOR inhibition prevents coronary artery remodeling in a murine model of Kawasaki disease

  • Arthritis Rheumatol. 2022 Sep 3. doi: 10.1002/art.42340.
Angus T Stock 1,  Sarah Parsons 2 3,  Damian B D'Silva 1,  Jacinta A Hansen 1,  Varun J Sharma 4 5 6,  Fiona James 7,  Graham Starkey 4 5,  Rohit D'Costa 8 9,  Claire L Gordon 7 10 11,  Ian P Wicks 1 12 13
Affiliations

Affiliations

  • 1 WEHI, Melbourne, 3052, Australia.
  • 2 Department of Forensic Medicine, Monash University, Melbourne, 3006, Australia.
  • 3 Victorian Institute of Forensic Medicine, Melbourne, 3006, Australia.
  • 4 Liver & Intestinal Transplant Unit, Austin Health, Melbourne, 3084, Australia.
  • 5 Department of Surgery, The University of Melbourne, Austin Health, Melbourne, 3084, Australia.
  • 6 Department of Cardiac Surgery, Austin Health, Melbourne, 3084, Australia.
  • 7 Department of Infectious Diseases, Austin Health, Melbourne, 3084, Australia.
  • 8 DonateLife Victoria, Carlton, 3053, Australia.
  • 9 Department of Intensive Care Medicine, Melbourne Health, Melbourne, 3084, Australia.
  • 10 Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 3052, Australia.
  • 11 North Eastern Public Health Unit, Austin Health, Melbourne, 3084, Australia.
  • 12 Rheumatology Unit, The Royal Melbourne Hospital, 3050, Australia.
  • 13 University of Melbourne, Department of Medical Biology, 3052, Australia.
PMID: 36057112 DOI: 10.1002/art.42340
Abstract

Objective: Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki Disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts which can lead to coronary artery aneurysms, stenosis and myocardial ischemia. We therefore investigated whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD.

Method: We used a murine model of KD (induced by the injection of the Candida albicans water soluble complex; CAWS) and analysis of patient samples to evaluate potential anti-fibrotic therapies for KD.

Results: We identified the mTOR pathway as a potential therapeutic target in KD. The mTOR Inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts upregulated mTOR kinase signaling in vivo during the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries upregulate mTOR signaling, confirming that the mTOR pathway is active in human KD.

Conclusions: Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high-risk KD patients. This article is protected by copyright. All rights reserved.

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