PMID- 24833660
OWN - NLM
STAT- MEDLINE
DCOM- 20140916
LR  - 20211203
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 115
IP  - 3
DP  - 2014 Jul 18
TI  - Cardiac-specific YAP activation improves cardiac function and survival in an 
      experimental murine MI model.
PG  - 354-63
LID - 10.1161/CIRCRESAHA.115.303632 [doi]
AB  - RATIONALE: Yes-associated protein (YAP), the terminal effector of the Hippo 
      signaling pathway, is crucial for regulating embryonic cardiomyocyte 
      proliferation. OBJECTIVE: We hypothesized that YAP activation after myocardial 
      infarction (MI) would preserve cardiac function and improve survival. METHODS AND 
      RESULTS: We used a cardiac-specific, inducible expression system to activate YAP 
      in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte 
      proliferation and did not deleteriously affect heart function. Furthermore, YAP 
      activation after MI preserved heart function and reduced infarct size. Using 
      adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human 
      YAP (hYAP) in the adult murine myocardium immediately after MI. We found that 
      AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP 
      did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, 
      AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling 
      indicated that AAV9:hYAP stimulated expression of cell cycle genes and promoted a 
      less mature cardiac gene expression signature. CONCLUSIONS: Cardiac-specific YAP 
      activation after MI mitigated myocardial injury, improved cardiac function, and 
      enhanced survival. These findings suggest that therapeutic activation of YAP or 
      its downstream targets, potentially through AAV-mediated gene therapy, may be a 
      strategy to improve outcome after MI.
CI  - (c) 2014 American Heart Association, Inc.
FAU - Lin, Zhiqiang
AU  - Lin Z
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - von Gise, Alexander
AU  - von Gise A
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Zhou, Pingzhu
AU  - Zhou P
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Gu, Fei
AU  - Gu F
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Ma, Qing
AU  - Ma Q
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Jiang, Jianming
AU  - Jiang J
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Yau, Allan L
AU  - Yau AL
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Buck, Jessica N
AU  - Buck JN
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Gouin, Katryna A
AU  - Gouin KA
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - van Gorp, Pim R R
AU  - van Gorp PR
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Zhou, Bin
AU  - Zhou B
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Chen, Jinghai
AU  - Chen J
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Seidman, Jonathan G
AU  - Seidman JG
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Wang, Da-Zhi
AU  - Wang DZ
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.).
FAU - Pu, William T
AU  - Pu WT
AD  - From the Departments of Cardiology, Boston Children's Hospital (Z.L., A.v.G., 
      P.Z., F.G., Q.M., A.L.Y., J.N.B., K.A.G., P.R.R.v.G., B.Z., J.C., D.-Z.W., 
      W.T.P.) and Genetics (J.J., J.G.S.), Harvard Medical School, Boston, MA; 
      Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical 
      School, Hannover, Germany (A.v.G.); Department of Cardiology, Leiden University 
      Medical Center, Leiden, The Netherlands (P.R.R.v.G.); Harvard Stem Cell 
      Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.); and Key 
      Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, China (B.Z.). wpu@enders.tch.harvard.edu.
LA  - eng
GR  - R01 HL116461/HL/NHLBI NIH HHS/United States
GR  - U01 HL100401/HL/NHLBI NIH HHS/United States
GR  - HL116461/HL/NHLBI NIH HHS/United States
GR  - HL100401/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140515
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Myh6 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factors)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (YAP1 protein, human)
RN  - EC 3.6.4.1 (Myosin Heavy Chains)
SB  - IM
CIN - Circ Res. 2014 Jul 18;115(3):332-4. PMID: 25035132
MH  - Adaptor Proteins, Signal Transducing/*genetics/*physiology
MH  - Animals
MH  - Apoptosis/genetics/physiology
MH  - Cardiomegaly
MH  - Cell Proliferation
MH  - Cell Survival/physiology
MH  - Dependovirus/genetics
MH  - Disease Models, Animal
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Myocardial Contraction/physiology
MH  - Myocardial Infarction/genetics/mortality/*physiopathology
MH  - Myocytes, Cardiac/cytology/*physiology
MH  - Myosin Heavy Chains/genetics
MH  - Phosphoproteins/*genetics/*physiology
MH  - Regeneration/genetics/physiology
MH  - Survival Rate
MH  - Transcription Factors
MH  - Transcriptome
MH  - YAP-Signaling Proteins
PMC - PMC4104149
MID - NIHMS596931
OTO - NOTNLM
OT  - heart failure
OT  - myocardial infarction
OT  - regeneration
OT  - survival
COIS- DISCLOSURES The authors have no conflicts of interest to disclose.
EDAT- 2014/05/17 06:00
MHDA- 2014/09/17 06:00
PMCR- 2015/07/18
CRDT- 2014/05/17 06:00
PHST- 2014/05/17 06:00 [entrez]
PHST- 2014/05/17 06:00 [pubmed]
PHST- 2014/09/17 06:00 [medline]
PHST- 2015/07/18 00:00 [pmc-release]
AID - CIRCRESAHA.115.303632 [pii]
AID - 10.1161/CIRCRESAHA.115.303632 [doi]
PST - ppublish
SO  - Circ Res. 2014 Jul 18;115(3):354-63. doi: 10.1161/CIRCRESAHA.115.303632. Epub 
      2014 May 15.