PMID- 36057112
OWN - NLM
STAT- MEDLINE
DCOM- 20230201
LR  - 20230214
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Linking)
VI  - 75
IP  - 2
DP  - 2023 Feb
TI  - Mechanistic Target of Rapamycin Inhibition Prevents Coronary Artery Remodeling in 
      a Murine Model of Kawasaki Disease.
PG  - 305-317
LID - 10.1002/art.42340 [doi]
AB  - 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 undertook this study to 
      investigate 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 analyzed patient samples to evaluate potential 
      antifibrotic therapies for KD. RESULTS: We identified the mechanistic target of 
      rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR 
      inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, 
      and vascular fibroblasts up-regulated mTOR kinase signaling in vivo in 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 up-regulate mTOR 
      signaling, confirming that the mTOR pathway is active in human KD. CONCLUSION: 
      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.
CI  - (c) 2022 American College of Rheumatology.
FAU - Stock, Angus T
AU  - Stock AT
AUID- ORCID: 0000-0002-3386-1857
AD  - Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 
      Australia.
FAU - Parsons, Sarah
AU  - Parsons S
AD  - Department of Forensic Medicine, Monash University, and Victorian Institute of 
      Forensic Medicine, Melbourne, Victoria, Australia.
FAU - D'Silva, Damian B
AU  - D'Silva DB
AD  - Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 
      Australia.
FAU - Hansen, Jacinta A
AU  - Hansen JA
AD  - Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 
      Australia.
FAU - Sharma, Varun J
AU  - Sharma VJ
AD  - Liver & Intestinal Transplant Unit, Department of Surgery, and Department of 
      Cardiac Surgery, The University of Melbourne, Austin Health, Melbourne, Victoria, 
      Australia.
FAU - James, Fiona
AU  - James F
AD  - Department of Infectious Diseases, Austin Health, Melbourne, Victoria, Australia.
FAU - Starkey, Graham
AU  - Starkey G
AD  - Liver & Intestinal Transplant Unit and Department of Surgery, The University of 
      Melbourne, Austin Health, Melbourne, Victoria, Australia.
FAU - D'Costa, Rohit
AU  - D'Costa R
AD  - DonateLife Victoria, Carlton, Victoria, Australia, and Department of Intensive 
      Care Medicine, Melbourne Health, Melbourne, Victoria, Australia.
FAU - Gordon, Claire L
AU  - Gordon CL
AD  - Department of Infectious Diseases, Austin Health, Department of Microbiology and 
      Immunology, The University of Melbourne, The Peter Doherty Institute for 
      Infection and Immunity, and North Eastern Public Health Unit, Austin Health, 
      Melbourne, Victoria, Australia.
FAU - Wicks, Ian P
AU  - Wicks IP
AD  - Walter and Eliza Hall Institute of Medical Research, Rheumatology Unit, The Royal 
      Melbourne Hospital, and University of Melbourne, Department of Medical Biology, 
      Victoria, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221220
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Mucocutaneous Lymph Node Syndrome/drug therapy
MH  - Coronary Vessels/pathology
MH  - Sirolimus/pharmacology
MH  - Disease Models, Animal
MH  - TOR Serine-Threonine Kinases
MH  - *Coronary Artery Disease
EDAT- 2022/09/04 06:00
MHDA- 2023/02/02 06:00
CRDT- 2022/09/03 13:22
PHST- 2022/06/23 00:00 [revised]
PHST- 2022/02/01 00:00 [received]
PHST- 2022/08/30 00:00 [accepted]
PHST- 2022/09/04 06:00 [pubmed]
PHST- 2023/02/02 06:00 [medline]
PHST- 2022/09/03 13:22 [entrez]
AID - 10.1002/art.42340 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2023 Feb;75(2):305-317. doi: 10.1002/art.42340. Epub 2022 
      Dec 20.