PMID- 37750561
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20240501
IS  - 2047-9980 (Electronic)
IS  - 2047-9980 (Linking)
VI  - 12
IP  - 19
DP  - 2023 Oct 3
TI  - An mTORC1-Dependent Mouse Model for Cardiac Sarcoidosis.
PG  - e030478
LID - 10.1161/JAHA.123.030478 [doi]
LID - e030478
AB  - Background Sarcoidosis is an inflammatory, granulomatous disease of unknown cause 
      affecting multiple organs, including the heart. Untreated, unresolved 
      granulomatous inflammation can lead to cardiac fibrosis, arrhythmias, and 
      eventually heart failure. Here we characterize the cardiac phenotype of mice with 
      chronic activation of mammalian target of rapamycin (mTOR) complex 1 signaling in 
      myeloid cells known to cause spontaneous pulmonary sarcoid-like granulomas. 
      Methods and Results The cardiac phenotype of mice with conditional deletion of 
      the tuberous sclerosis 2 (TSC2) gene in CD11c(+) cells (TSC2(fl/fl)CD11c-Cre; 
      termed TSC2(KO)) and controls (TSC2(fl/fl)) was determined by histological and 
      immunological stains. Transthoracic echocardiography and invasive hemodynamic 
      measurements were performed to assess myocardial function. TSC2(KO) animals were 
      treated with either everolimus, an mTOR inhibitor, or Bay11-7082, a nuclear 
      factor-kB inhibitor. Activation of mTOR signaling was evaluated on myocardial 
      samples from sudden cardiac death victims with a postmortem diagnosis of cardiac 
      sarcoidosis. Chronic activation of mTORC1 signaling in CD11c(+) cells was 
      sufficient to initiate progressive accumulation of granulomatous infiltrates in 
      the heart, which was associated with increased fibrosis, impaired cardiac 
      function, decreased plakoglobin expression, and abnormal connexin 43 
      distribution, a substrate for life-threatening arrhythmias. Mice treated with the 
      mTOR inhibitor everolimus resolved granulomatous infiltrates, prevented fibrosis, 
      and improved cardiac dysfunction. In line, activation of mTOR signaling in 
      CD68(+) macrophages was detected in the hearts of sudden cardiac death victims 
      who suffered from cardiac sarcoidosis. Conclusions To our best knowledge this is 
      the first animal model of cardiac sarcoidosis that recapitulates major 
      pathological hallmarks of human disease. mTOR inhibition may be a therapeutic 
      option for patients with cardiac sarcoidosis.
FAU - Bueno-Beti, Carlos
AU  - Bueno-Beti C
AUID- ORCID: 0000-0003-4626-1276
AD  - Clinical Cardiology Academic Group, Molecular and Clinical Research Science 
      Institute St George's University of London London United Kingdom.
FAU - Lim, Clarice X
AU  - Lim CX
AUID- ORCID: 0000-0001-7297-0055
AD  - Center for Pathobiochemistry and Genetics Medical University of Vienna Vienna 
      Austria.
FAU - Protonotarios, Alexandros
AU  - Protonotarios A
AUID- ORCID: 0000-0001-8595-7212
AD  - Institute of Cardiovascular Science, Clinical Science Research Group University 
      College London London United Kingdom.
FAU - Szabo, Petra Lujza
AU  - Szabo PL
AUID- ORCID: 0000-0001-5465-8391
AD  - Center for Biomedical Research Medical University of Vienna Vienna Austria.
FAU - Westaby, Joseph
AU  - Westaby J
AUID- ORCID: 0000-0002-1903-2390
AD  - Clinical Cardiology Academic Group, Molecular and Clinical Research Science 
      Institute St George's University of London London United Kingdom.
FAU - Mazic, Mario
AU  - Mazic M
AUID- ORCID: 0000-0002-2385-1866
AD  - Center for Pathobiochemistry and Genetics Medical University of Vienna Vienna 
      Austria.
FAU - Sheppard, Mary N
AU  - Sheppard MN
AUID- ORCID: 0000-0003-2724-3881
AD  - Clinical Cardiology Academic Group, Molecular and Clinical Research Science 
      Institute St George's University of London London United Kingdom.
FAU - Behr, Elijah
AU  - Behr E
AUID- ORCID: 0000-0002-8731-2853
AD  - Clinical Cardiology Academic Group, Molecular and Clinical Research Science 
      Institute St George's University of London London United Kingdom.
FAU - Hamza, Ouafa
AU  - Hamza O
AUID- ORCID: 0000-0002-3025-7064
AD  - Center for Biomedical Research Medical University of Vienna Vienna Austria.
FAU - Kiss, Attila
AU  - Kiss A
AD  - Center for Biomedical Research Medical University of Vienna Vienna Austria.
FAU - Podesser, Bruno K
AU  - Podesser BK
AUID- ORCID: 0000-0002-4641-7202
AD  - Center for Biomedical Research Medical University of Vienna Vienna Austria.
FAU - Hengstschlager, Markus
AU  - Hengstschlager M
AUID- ORCID: 0000-0002-3342-7583
AD  - Center for Pathobiochemistry and Genetics Medical University of Vienna Vienna 
      Austria.
FAU - Weichhart, Thomas
AU  - Weichhart T
AUID- ORCID: 0000-0002-4349-0797
AD  - Center for Pathobiochemistry and Genetics Medical University of Vienna Vienna 
      Austria.
FAU - Asimaki, Angeliki
AU  - Asimaki A
AUID- ORCID: 0000-0001-9886-6870
AD  - Clinical Cardiology Academic Group, Molecular and Clinical Research Science 
      Institute St George's University of London London United Kingdom.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - 208460/Z/17/Z/WT_/Wellcome Trust/United Kingdom
GR  - PG/18/27/33616/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230926
PL  - England
TA  - J Am Heart Assoc
JT  - Journal of the American Heart Association
JID - 101580524
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - 0 (Multiprotein Complexes)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Death, Sudden, Cardiac
MH  - Disease Models, Animal
MH  - Everolimus
MH  - Fibrosis
MH  - Mammals/metabolism
MH  - *Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Multiprotein Complexes/metabolism
MH  - Myocarditis/genetics/metabolism
MH  - *Sarcoidosis/metabolism/pathology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tuberous Sclerosis Complex 2 Protein/genetics/metabolism
MH  - Tumor Suppressor Proteins/genetics
MH  - *Cardiomyopathies/genetics/metabolism
PMC - PMC10727264
OTO - NOTNLM
OT  - cardiac sarcoidosis
OT  - fibrosis
OT  - heart
OT  - mTORC1
OT  - mouse model
OT  - sarcoidosis
EDAT- 2023/09/26 13:43
MHDA- 2023/10/23 01:18
PMCR- 2023/10/03
CRDT- 2023/09/26 08:03
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/09/26 13:43 [pubmed]
PHST- 2023/09/26 08:03 [entrez]
PHST- 2023/10/03 00:00 [pmc-release]
AID - JAH38803 [pii]
AID - 10.1161/JAHA.123.030478 [doi]
PST - ppublish
SO  - J Am Heart Assoc. 2023 Oct 3;12(19):e030478. doi: 10.1161/JAHA.123.030478. Epub 
      2023 Sep 26.