Cardiac remodeling caused by transgenic overexpression of a corn Rac gene
| Autor: | Leni Moldovan, Osama El-Sayed, Mazin A. Alhaj, Mohammad T. Elnakish, Muzzammil Sayyid, Lucas Citro, Mohamed M Awad, Mohamed Darwish Hessein Hassona, Periannan Kuppusamy, Zeinb A. Abouelnaga, Hamdy H. Hassanain, Aditi C. Kulkarni, Mahmood Khan |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Genetically modified mouse
Male rac1 GTP-Binding Protein medicine.medical_specialty Aging Genotype Physiology MAP Kinase Signaling System Transgene Integrin alpha1 Molecular Sequence Data Constitutively active Mice Transgenic Biology Ventricular Function Left Mice Ventricular Dysfunction Left Superoxides Physiology (medical) Complementary DNA Internal medicine medicine Animals Amino Acid Sequence Promoter Regions Genetic Gene Plant Proteins Pravastatin chemistry.chemical_classification Reactive oxygen species Analysis of Variance Myosin Heavy Chains Ventricular Remodeling Integrin beta1 Myocardium Magnetic Resonance Imaging Cell biology Thyroxine Endocrinology Phenotype chemistry Echocardiography Mutation Hypertrophy Left Ventricular Cardiology and Cardiovascular Medicine |
| Zdroj: | American journal of physiology. Heart and circulatory physiology. 301(3) |
| ISSN: | 1522-1539 |
| Popis: | 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 α1-integrin (224%) and β1-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|