PMID- 36988388
OWN - NLM
STAT- MEDLINE
DCOM- 20230815
LR  - 20230815
IS  - 1521-6551 (Electronic)
IS  - 1521-6543 (Linking)
VI  - 75
IP  - 9
DP  - 2023 Sep
TI  - Rapamycin treatment unmasks a sex-specific pattern of scar expansion of the 
      infarcted rat heart: The relationship between mTOR and K(ATP) channel.
PG  - 717-731
LID - 10.1002/iub.2722 [doi]
AB  - Inhibition of the mammalian target of rapamycin (mTOR) with the macrolide 
      rapamycin or pharmacological suppression of K(ATP) channel opening translated to 
      scar expansion of the myocardial infarcted (MI) adult female rodent heart. The 
      present study tested the hypotheses that rapamycin-mediated scar expansion was 
      sex-specific and that mTOR signaling directly influenced K(ATP) channel subunit 
      expression/activity. Scar size was significantly larger in post-MI male rats as 
      compared to the previous data reported in post-MI female rats. The reported scar 
      expansion of rapamycin-treated post-MI female rats was not observed following the 
      administration of the macrolide to post-MI male rats. Protein levels of the 
      K(ATP) channel subunits Kir6.2 and SUR2A and phosphorylation of the serine(2448) 
      residue of mTOR were similar in the normal heart of adult male and female rats. 
      By contrast, greater tuberin inactivation characterized by the increased 
      phosphorylation of the threonine(1462) residue and reduced raptor protein levels 
      were identified in the normal heart of adult female rats. Rapamycin pretreatment 
      of phorbol 12,13-dibutyrate (PDBu)-treated neonatal rat ventricular 
      cardiomyocytes (NNVMs) suppressed hypertrophy, inhibited p70S6K phosphorylation, 
      and attenuated SUR2A protein upregulation. In the presence of low ATP levels, 
      K(ATP) channel activity detected in untreated NNVMs was significantly attenuated 
      in PDBu-induced hypertrophied NNVMs via a rapamycin-independent pathway. Thus, 
      rapamycin administration to post-MI rats unmasked a sex-specific pattern of scar 
      expansion and mTOR signaling in PDBu-induced hypertrophied NNVMs significantly 
      increased SUR2A protein levels. However, the biological advantage associated with 
      SUR2A protein upregulation was partially offset by an mTOR-independent pathway 
      that attenuated K(ATP) channel activity in PDBu-induced hypertrophied NNVMs.
CI  - (c) 2023 International Union of Biochemistry and Molecular Biology.
FAU - Al-Katat, Aya
AU  - Al-Katat A
AD  - Research Center, Montreal Heart Institute and Universite de Montreal, Montreal, 
      Quebec, Canada.
AD  - Departement de Pharmacologie et Physiologie, Universite de Montreal, Montreal, 
      Quebec, Canada.
FAU - Bergeron, Alexandre
AU  - Bergeron A
AD  - Research Center, Montreal Heart Institute and Universite de Montreal, Montreal, 
      Quebec, Canada.
FAU - Parent, Lucie
AU  - Parent L
AD  - Research Center, Montreal Heart Institute and Universite de Montreal, Montreal, 
      Quebec, Canada.
AD  - Departement de Pharmacologie et Physiologie, Universite de Montreal, Montreal, 
      Quebec, Canada.
FAU - Lorenzini, Maxime
AU  - Lorenzini M
AD  - Research Center, Montreal Heart Institute and Universite de Montreal, Montreal, 
      Quebec, Canada.
FAU - Fiset, Celine
AU  - Fiset C
AD  - Research Center, Montreal Heart Institute and Universite de Montreal, Montreal, 
      Quebec, Canada.
AD  - Faculte de Pharmacie, Universite de Montreal, Montreal, Quebec, Canada.
FAU - Calderone, Angelino
AU  - Calderone A
AUID- ORCID: 0000-0002-4170-5950
AD  - Research Center, Montreal Heart Institute and Universite de Montreal, Montreal, 
      Quebec, Canada.
AD  - Departement de Pharmacologie et Physiologie, Universite de Montreal, Montreal, 
      Quebec, Canada.
LA  - eng
GR  - PGT-168859/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230329
PL  - England
TA  - IUBMB Life
JT  - IUBMB life
JID - 100888706
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Macrolides)
RN  - 0 (Anti-Bacterial Agents)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (mTOR protein, rat)
SB  - IM
MH  - Female
MH  - Male
MH  - Animals
MH  - Rats
MH  - *Sirolimus/pharmacology
MH  - Cicatrix
MH  - TOR Serine-Threonine Kinases/genetics
MH  - *Myocardial Infarction/drug therapy/genetics
MH  - Macrolides
MH  - Anti-Bacterial Agents
MH  - Adenosine Triphosphate
MH  - Mammals
OTO - NOTNLM
OT  - KATP channels
OT  - mTOR
OT  - myocardial infarction
OT  - rapamycin
OT  - sex
EDAT- 2023/03/30 06:00
MHDA- 2023/08/15 06:42
CRDT- 2023/03/29 09:23
PHST- 2023/01/02 00:00 [received]
PHST- 2023/02/24 00:00 [accepted]
PHST- 2023/08/15 06:42 [medline]
PHST- 2023/03/30 06:00 [pubmed]
PHST- 2023/03/29 09:23 [entrez]
AID - 10.1002/iub.2722 [doi]
PST - ppublish
SO  - IUBMB Life. 2023 Sep;75(9):717-731. doi: 10.1002/iub.2722. Epub 2023 Mar 29.