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 Rnd3(+/-) 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.
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yue
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: X
authors.initials: X
authors.lastname: Yi
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China.
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.affiliation: Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: G-C
authors.initials: GC
authors.lastname: Fan
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D057895:Haploinsufficiency; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C513341:Rnd3 protein, mouse; D020741:rho GTP-Binding Proteins