Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.
BACKGROUND
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.


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.
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.).
Zhiqiang
Z
Lin
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.).
Alexander
A
von Gise
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.).
Pingzhu
P
Zhou
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.).
Fei
F
Gu
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.).
Qing
Q
Ma
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.).
Jianming
J
Jiang
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.).
Allan L
AL
Yau
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.).
Jessica N
JN
Buck
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.).
Katryna A
KA
Gouin
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.).
Pim R R
PR
van Gorp
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.).
Bin
B
Zhou
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.).
Jinghai
J
Chen
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.).
Jonathan G
JG
Seidman
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.).
Da-Zhi
DZ
Wang
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.
William T
WT
Pu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D006332:Cardiomegaly; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D015996:Survival Rate; D014157:Transcription Factors; D059467:Transcriptome; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C584019:Myh6 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D018995:Myosin Heavy Chains
heart failure; myocardial infarction; regeneration; survival