PMID- 27158672
OWN - NLM
STAT- Publisher
LR  - 20191120
IS  - 2379-3708 (Print)
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 1
IP  - 4
DP  - 2016 Apr 6
TI  - Functional significance of the discordance between transcriptional profile and 
      left ventricular structure/function during reverse remodeling.
PG  - e86038
LID - e86038
AB  - To elucidate the mechanisms for reverse LV remodeling, we generated a conditional 
      (doxycycline [dox] off) transgenic mouse tetracycline transactivating 
      factor-TRAF2 (tTA-TRAF2) that develops a dilated heart failure (HF) phenotype 
      upon expression of a proinflammatory transgene, TNF receptor-associated factor 2 
      (TRAF2), and complete normalization of LV structure and function when the 
      transgene is suppressed. tTA-TRAF2 mice developed a significant increase in LV 
      dimension with decreased contractile function, which was completely normalized in 
      the tTA-TRAF2 mice fed dox for 4 weeks (tTA-TRAF2(dox4W)). Normalization of LV 
      structure and function was accompanied by partial normalization (~60%) of gene 
      expression associated with incident HF. Similar findings were observed in 
      patients with dilated cardiomyopathy who underwent reverse LV remodeling 
      following mechanical circulatory support. Persistence of the HF gene program was 
      associated with an exaggerated hypertrophic response and increased mortality in 
      tTA-TRAF2(dox4W) mice following transaortic constriction (TAC). These effects 
      were no longer observed following TAC in tTA-TRAF2(dox8W), wherein there was a 
      more complete (88%) reversal of the incident HF genes. These results demonstrate 
      that reverse LV remodeling is associated with improvements in cardiac myocyte 
      biology; however, the persistence of the abnormal HF gene program may be 
      maladaptive following perturbations in hemodynamic loading conditions.
FAU - Topkara, Veli K
AU  - Topkara VK
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Chambers, Kari T
AU  - Chambers KT
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Yang, Kai-Chien
AU  - Yang KC
AD  - Department of Pharmacology, National Taiwan University School of Medicine, 
      Taipei, Taiwan.
FAU - Tzeng, Huei-Ping
AU  - Tzeng HP
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Evans, Sarah
AU  - Evans S
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Weinheimer, Carla
AU  - Weinheimer C
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Kovacs, Attila
AU  - Kovacs A
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Robbins, Jeffrey
AU  - Robbins J
AD  - Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's 
      Hospital, Cincinnati, Ohio, USA.
FAU - Barger, Philip
AU  - Barger P
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
FAU - Mann, Douglas L
AU  - Mann DL
AD  - Center for Cardiovascular Research, Division of Cardiology, Department of 
      Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
LA  - eng
GR  - P01 HL069779/HL/NHLBI NIH HHS/United States
GR  - T32 HL007081/HL/NHLBI NIH HHS/United States
GR  - R01 HL089543/HL/NHLBI NIH HHS/United States
GR  - R01 HL058081/HL/NHLBI NIH HHS/United States
GR  - R01 HL073017/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
PMC - PMC4855517
MID - NIHMS777086
EDAT- 2016/05/10 06:00
MHDA- 2016/05/10 06:00
PMCR- 2016/04/07
CRDT- 2016/05/10 06:00
PHST- 2016/05/10 06:00 [entrez]
PHST- 2016/05/10 06:00 [pubmed]
PHST- 2016/05/10 06:00 [medline]
PHST- 2016/04/07 00:00 [pmc-release]
AID - 86038 [pii]
AID - 10.1172/jci.insight.86038 [doi]
PST - ppublish
SO  - JCI Insight. 2016 Apr 6;1(4):e86038. doi: 10.1172/jci.insight.86038.