PMID- 32670093
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240329
IS  - 1664-042X (Print)
IS  - 1664-042X (Electronic)
IS  - 1664-042X (Linking)
VI  - 11
DP  - 2020
TI  - Exogenous Cardiac Bridging Integrator 1 Benefits Mouse Hearts With Pre-existing 
      Pressure Overload-Induced Heart Failure.
PG  - 708
LID - 10.3389/fphys.2020.00708 [doi]
LID - 708
AB  - Background: Cardiac bridging integrator 1 (cBIN1) organizes transverse tubule 
      (t-tubule) membrane calcium handling microdomains required for normal 
      beat-to-beat contractility. cBIN1 is transcriptionally reduced in heart failure 
      (HF). We recently found that cBIN1 pretreatment can limit HF development in 
      stressed mice. Here, we aim to explore whether cBIN1 replacement therapy can 
      improve myocardial function in continuously stressed hearts with pre-existing HF. 
      Methods: Adult male mice were subjected to sham or transverse aortic constriction 
      (TAC) surgery at the age of 8-10 weeks old. Adeno-associated virus 9 (AAV9) 
      transducing cBIN1-V5 or GFP-V5 (3 x 10(10) vg) was administered through 
      retro-orbital injection at 5 weeks post-TAC. Mice were followed by 
      echocardiography to monitor cardiac function until 20 weeks after TAC. Overall 
      survival, heart and lung weight (LW), and HF incidence were determined. In a 
      second set of animals in which AAV9-cBIN1 pretreatment prevents HF, we recorded 
      cardiac pressure-volume (PV) loops and obtained myocardial immunofluorescence 
      imaging. Results: The overall Kaplan-Meir survival of AAV9-cBIN1 mice was 77.8%, 
      indicating a significant partial rescue between AAV9-GFP (58.8%) and sham (100%) 
      treated mice. In mice with ejection fraction (EF) >/=30% prior to AAV9 injection at 
      5 weeks post-TAC, AAV9-cBIN1 significantly increased survival to 93.3%, compared 
      to 62.5% survival for AAV9-GFP treated mice. The effect of exogenous cBIN1 was to 
      attenuate TAC-induced left ventricular (LV) dilation and prevent further HF 
      development. Recovery of EF also occurs in AAV9-cBIN1-treated mice. We found that 
      EF increases to a peak at 6-8 weeks post-viral injection. Furthermore, PV loop 
      analysis identified that AAV9-cBIN1 increases both systolic and diastolic 
      function of the post-TAC hearts. At the myocyte level, AAV9-cBIN1 normalizes 
      cBIN1 expression, t-tubule membrane intensity, and intracellular distribution of 
      Cav1.2 and ryanodine receptors (RyRs). Conclusions: In mice with pre-existing HF, 
      exogenous cBIN1 can normalize t-tubule calcium handling microdomains, limit HF 
      progression, rescue cardiac function, and improve survival.
CI  - Copyright (c) 2020 Li, Agvanian, Zhou, Shaw and Hong.
FAU - Li, Jing
AU  - Li J
AD  - Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los 
      Angeles, CA, United States.
FAU - Agvanian, Sosse
AU  - Agvanian S
AD  - Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los 
      Angeles, CA, United States.
FAU - Zhou, Kang
AU  - Zhou K
AD  - Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los 
      Angeles, CA, United States.
FAU - Shaw, Robin M
AU  - Shaw RM
AD  - Nora Eccles Harrison Cardiovascular Research and Training Institute, University 
      of Utah, Salt Lake City, UT, United States.
FAU - Hong, TingTing
AU  - Hong T
AD  - Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los 
      Angeles, CA, United States.
AD  - Nora Eccles Harrison Cardiovascular Research and Training Institute, University 
      of Utah, Salt Lake City, UT, United States.
AD  - Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, 
      Salt Lake City, UT, United States.
LA  - eng
GR  - R01 HL133286/HL/NHLBI NIH HHS/United States
GR  - R01 HL138577/HL/NHLBI NIH HHS/United States
GR  - R01 HL152691/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20200624
PL  - Switzerland
TA  - Front Physiol
JT  - Frontiers in physiology
JID - 101549006
PMC - PMC7327113
OTO - NOTNLM
OT  - calcium handling
OT  - cardiac bridging integrator 1
OT  - gene therapy
OT  - heart failure
OT  - ion channel
EDAT- 2020/07/17 06:00
MHDA- 2020/07/17 06:01
PMCR- 2020/06/24
CRDT- 2020/07/17 06:00
PHST- 2020/04/01 00:00 [received]
PHST- 2020/05/29 00:00 [accepted]
PHST- 2020/07/17 06:00 [entrez]
PHST- 2020/07/17 06:00 [pubmed]
PHST- 2020/07/17 06:01 [medline]
PHST- 2020/06/24 00:00 [pmc-release]
AID - 10.3389/fphys.2020.00708 [doi]
PST - epublish
SO  - Front Physiol. 2020 Jun 24;11:708. doi: 10.3389/fphys.2020.00708. eCollection 
      2020.