Cardiac remodeling caused by transgenic overexpression of a corn Rac gene

• Published in: American journal of physiology. Heart and circulatory physiology 2011-09, Vol.301 (3), p.H868-H880
• Main Authors: Elnakish, Mohammad T, Awad, Mohamed M, Hassona, Mohamed D H, Alhaj, Mazin A, Kulkarni, Aditi, Citro, Lucas A, Sayyid, Muzzammil, Abouelnaga, Zeinb A, El-Sayed, Osama, Kuppusamy, Periannan, Moldovan, Leni, Khan, Mahmood, Hassanain, Hamdy H
• Format: Article
• Language: English
• Subjects: Aging; Amino Acid Sequence; Analysis of Variance; Animals; Echocardiography; Gene expression; Genes; Genotype; Heart; Hypertrophy, Left Ventricular - diagnosis; Hypertrophy, Left Ventricular - enzymology; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - physiopathology; Integrin alpha1 - metabolism; Integrin beta1 - metabolism; Magnetic Resonance Imaging; Male; MAP Kinase Signaling System; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Myocardium - enzymology; Myocardium - pathology; Myosin Heavy Chains - genetics; Phenotype; Plant Proteins - antagonists & inhibitors; Plant Proteins - genetics; Plant Proteins - metabolism; Pravastatin - pharmacology; Promoter Regions, Genetic; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rodents; Statins; Superoxides - metabolism; Thyroxine - pharmacology; Ventricular Dysfunction, Left - diagnosis; Ventricular Dysfunction, Left - enzymology; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - physiopathology; Ventricular Function, Left - drug effects; Ventricular Function, Left - genetics; Ventricular Remodeling - drug effects; Ventricular Remodeling - genetics
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00807.2010

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.