Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure

X. Yue, X. Yang, X. Lin, T. Yang, X. Yi, Y. Dai, J. Guo, T. Li, Jianjian Shi, Lei Wei, G. C. Fan, C. Chen, J. Chang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/- haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/- mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd +/-haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/- mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/-/ROCK1-/-). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.

Original languageEnglish
Article numbere1284
JournalCell Death and Disease
Volume5
Issue number6
DOIs
StatePublished - 2014

Fingerprint

rho-Associated Kinases
Cardiomyopathies
Heart Failure
Hemodynamics
Guanosine
Down-Regulation
Apoptosis
Haploinsufficiency
Actin Cytoskeleton
Constriction
Knockout Mice
Caspase 3
Cell Movement
Pharmacology
Phenotype
Pressure

Keywords

  • Apoptotic cardiomyopathy
  • Heart failure
  • Rho family GTPase 3
  • Rho kinase signaling

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure. / Yue, X.; Yang, X.; Lin, X.; Yang, T.; Yi, X.; Dai, Y.; Guo, J.; Li, T.; Shi, Jianjian; Wei, Lei; Fan, G. C.; Chen, C.; Chang, J.

In: Cell Death and Disease, Vol. 5, No. 6, e1284, 2014.

Research output: Contribution to journalArticle

Yue, X. ; Yang, X. ; Lin, X. ; Yang, T. ; Yi, X. ; Dai, Y. ; Guo, J. ; Li, T. ; Shi, Jianjian ; Wei, Lei ; Fan, G. C. ; Chen, C. ; Chang, J. / Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure. In: Cell Death and Disease. 2014 ; Vol. 5, No. 6.
@article{0645a32d8baf44b781d2b81fc058dbc4,
title = "Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure",
abstract = "Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/- haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/- mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd +/-haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/- mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/-/ROCK1-/-). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.",
keywords = "Apoptotic cardiomyopathy, Heart failure, Rho family GTPase 3, Rho kinase signaling",
author = "X. Yue and X. Yang and X. Lin and T. Yang and X. Yi and Y. Dai and J. Guo and T. Li and Jianjian Shi and Lei Wei and Fan, {G. C.} and C. Chen and J. Chang",
year = "2014",
doi = "10.1038/cddis.2014.235",
language = "English",
volume = "5",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure

AU - Yue, X.

AU - Yang, X.

AU - Lin, X.

AU - Yang, T.

AU - Yi, X.

AU - Dai, Y.

AU - Guo, J.

AU - Li, T.

AU - Shi, Jianjian

AU - Wei, Lei

AU - Fan, G. C.

AU - Chen, C.

AU - Chang, J.

PY - 2014

Y1 - 2014

N2 - Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/- haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/- mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd +/-haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/- mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/-/ROCK1-/-). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.

AB - Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/- haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/- mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd +/-haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/- mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/-/ROCK1-/-). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.

KW - Apoptotic cardiomyopathy

KW - Heart failure

KW - Rho family GTPase 3

KW - Rho kinase signaling

UR - http://www.scopus.com/inward/record.url?scp=84903776347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903776347&partnerID=8YFLogxK

U2 - 10.1038/cddis.2014.235

DO - 10.1038/cddis.2014.235

M3 - Article

C2 - 24901055

AN - SCOPUS:84903776347

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 6

M1 - e1284

ER -