title: Cardiac remodeling caused by transgenic overexpression of a corn Rac gene.
abstract: Rac1-GTPase activation plays a key role in the development and progression of cardiac remodeling. Therefore, we engineered a transgenic mouse model by overexpressing cDNA of a constitutively active form of Zea maize Rac gene (ZmRacD) specifically in the hearts of FVB/N mice. Echocardiography and MRI analyses showed cardiac hypertrophy in old transgenic mice, as evidenced by increased left ventricular (LV) mass and LV mass-to-body weight ratio, which are associated with relative ventricular chamber dilation and systolic dysfunction. LV hypertrophy in the hearts of old transgenic mice was further confirmed by an increased heart weight-to-body weight ratio and histopathology analysis. The cardiac remodeling in old transgenic mice was coupled with increased myocardial Rac-GTPase activity (372%) and ROS production (462%). There were also increases in α(1)-integrin (224%) and β(1)-integrin (240%) expression. This led to the activation of hypertrophic signaling pathways, e.g., ERK1/2 (295%) and JNK (223%). Pravastatin treatment led to inhibition of Rac-GTPase activity and integrin signaling. Interestingly, activation of ZmRacD expression with thyroxin led to cardiac dilation and systolic dysfunction in adult transgenic mice within 2 wk. In conclusion, this is the first study to show the conservation of Rho/Rac proteins between plant and animal kingdoms in vivo. Additionally, ZmRacD is a novel transgenic model that gradually develops a cardiac phenotype with aging. Furthermore, the shift from cardiac hypertrophy to dilated hearts via thyroxin treatment will provide us with an excellent system to study the temporal changes in cardiac signaling from adaptive to maladaptive hypertrophy and heart failure.
authors.affiliation: Department of Anesthesiology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Mohammad T
authors.initials: MT
authors.lastname: Elnakish
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Awad
authors.forename: Mohamed D H
authors.initials: MD
authors.lastname: Hassona
authors.forename: Mazin A
authors.initials: MA
authors.lastname: Alhaj
authors.forename: Aditi
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Citro
authors.forename: Muzzammil
authors.initials: M
authors.lastname: Sayyid
authors.forename: Zeinb A
authors.initials: ZA
authors.lastname: Abouelnaga
authors.forename: Osama
authors.initials: O
authors.lastname: El-Sayed
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.forename: Leni
authors.initials: L
authors.lastname: Moldovan
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Hamdy H
authors.initials: HH
authors.lastname: Hassanain
mesh_terms: D000375:Aging; D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000818:Animals; D004452:Echocardiography; D005838:Genotype; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D039423:Integrin alpha1 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D013481:Superoxides / Q000378:metabolism; D013974:Thyroxine / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000235:genetics; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D039423:Integrin alpha1; D019012:Integrin beta1; D010940:Plant Proteins; D013481:Superoxides; D018995:Myosin Heavy Chains; D020830:rac1 GTP-Binding Protein; D017035:Pravastatin; D013974:Thyroxine