PMID- 22558250
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - Heart failure-inducible gene therapy targeting protein phosphatase 1 prevents 
      progressive left ventricular remodeling.
PG  - e35875
LID - 10.1371/journal.pone.0035875 [doi]
LID - e35875
AB  - BACKGROUND: The targeting of Ca(2+) cycling has emerged as a potential therapy 
      for the treatment of severe heart failure. These approaches include gene therapy 
      directed at overexpressing sarcoplasmic reticulum (SR) Ca(2+) ATPase, or ablation 
      of phospholamban (PLN) and associated protein phosphatase 1 (PP1) protein 
      complexes. We previously reported that PP1beta, one of the PP1 catalytic subunits, 
      predominantly suppresses Ca(2+) uptake in the SR among the three PP1 isoforms, 
      thereby contributing to Ca(2+) downregulation in failing hearts. In the present 
      study, we investigated whether heart-failure-inducible PP1beta-inhibition by 
      adeno-associated viral-9 (AAV9) vector mediated gene therapy is beneficial for 
      preventing disease progression in genetic cardiomyopathic mice. METHODS: We 
      created an adeno-associated virus 9 (AAV9) vector encoding PP1beta short-hairpin RNA 
      (shRNA) or negative control (NC) shRNA. A heart failure inducible gene expression 
      system was employed using the B-type natriuretic protein (BNP) promoter 
      conjugated to emerald-green fluorescence protein (EmGFP) and the shRNA sequence. 
      AAV9 vectors (AAV9-BNP-EmGFP-PP1betashRNA and AAV9-BNP-EmGFP-NCshRNA) were injected 
      into the tail vein (2x10(11) GC/mouse) of muscle LIM protein deficient mice 
      (MLPKO), followed by serial analysis of echocardiography, hemodynamic 
      measurement, biochemical and histological analysis at 3 months. RESULTS: In the 
      MLPKO mice, BNP promoter activity was shown to be increased by detecting both 
      EmGFP expression and the induced reduction of PP1beta by 25% in the myocardium. 
      Inducible PP1betashRNA delivery preferentially ameliorated left ventricular 
      diastolic function and mitigated adverse ventricular remodeling. PLN 
      phosphorylation was significantly augmented in the AAV9-BNP-EmGFP-PP1betashRNA 
      injected hearts compared with the AAV9-BNP-EmGFP-NCshRNA group. Furthermore, BNP 
      production was reduced, and cardiac interstitial fibrosis was abrogated at 3 
      months. CONCLUSION: Heart failure-inducible molecular targeting of PP1beta has 
      potential as a novel therapeutic strategy for heart failure.
FAU - Miyazaki, Yosuke
AU  - Miyazaki Y
AD  - Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi 
      University Graduate School of Medicine, Ube, Japan.
FAU - Ikeda, Yasuhiro
AU  - Ikeda Y
FAU - Shiraishi, Kozo
AU  - Shiraishi K
FAU - Fujimoto, Shizuka N
AU  - Fujimoto SN
FAU - Aoyama, Hidekazu
AU  - Aoyama H
FAU - Yoshimura, Koichi
AU  - Yoshimura K
FAU - Inui, Makoto
AU  - Inui M
FAU - Hoshijima, Masahiko
AU  - Hoshijima M
FAU - Kasahara, Hideko
AU  - Kasahara H
FAU - Aoki, Hiroki
AU  - Aoki H
FAU - Matsuzaki, Masunori
AU  - Matsuzaki M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120427
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Isoenzymes)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (phospholamban)
RN  - 114471-18-0 (Natriuretic Peptide, Brain)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
SB  - IM
MH  - Animals
MH  - Calcium Signaling/genetics
MH  - Calcium-Binding Proteins/antagonists & inhibitors/metabolism
MH  - Cardiomyopathies/genetics/metabolism/therapy
MH  - Dependovirus/*genetics
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Green Fluorescent Proteins/genetics
MH  - Heart Failure/genetics/metabolism/*therapy
MH  - Isoenzymes/antagonists & inhibitors/genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Myocardium/*metabolism/pathology
MH  - Natriuretic Peptide, Brain/genetics
MH  - Promoter Regions, Genetic
MH  - Protein Phosphatase 1/*antagonists & inhibitors/genetics/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
MH  - Ventricular Remodeling/*genetics
PMC - PMC3338799
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/05/05 06:00
MHDA- 2012/09/14 06:00
PMCR- 2012/04/27
CRDT- 2012/05/05 06:00
PHST- 2011/11/27 00:00 [received]
PHST- 2012/03/23 00:00 [accepted]
PHST- 2012/05/05 06:00 [entrez]
PHST- 2012/05/05 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
PHST- 2012/04/27 00:00 [pmc-release]
AID - PONE-D-11-23769 [pii]
AID - 10.1371/journal.pone.0035875 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e35875. doi: 10.1371/journal.pone.0035875. Epub 2012 Apr 27.