Cardiac remodeling caused by transgenic overexpression of a corn Rac gene

Author:

Elnakish Mohammad T.1234,Awad Mohamed M.124,Hassona Mohamed D. H.1254,Alhaj Mazin A.12,Kulkarni Aditi267,Citro Lucas A.267,Sayyid Muzzammil26,Abouelnaga Zeinb A.12,El-Sayed Osama6,Kuppusamy Periannan267,Moldovan Leni28,Khan Mahmood236,Hassanain Hamdy H.123

Affiliation:

1. Department of Anesthesiology,

2. Dorothy M. Davis Heart and Lung Research Institute,

3. Molecular, Cellular, and Developmental Biology Program,

4. Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt

5. Biochemistry Program,

6. Department of Internal Medicine,

7. Biophysics Graduate Program,

8. Department of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, Ohio; and

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 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.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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