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.

Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury

“…Consistent with these findings, it has been reported that increased endogenous myocardial Rac/NADPH oxidase activity in aging rats causes cardiomyocyte hypertrophy and cardiac remodeling (57). Interestingly, the activation of myocardial ZmRacD along with endogenous Rac expression with thyroxine treatment led to cardiac dilation and severe systolic dysfunction in young adult transgenic mice (19,20). Thus a potential molecular link exists between increased Rac activity and myocardial susceptibility to cardiac pathologies.…”

“…Aging caused markedly higher levels of myocardial Rac expression and Rac-GTPase activity in ZmRacD transgenic mice (19). Importantly, while normal at young age, with aging these TG mice develop a distinct cardiac phenotype manifested by cardiac hypertrophy, relative ventricular chamber dilation, and moderate systolic dysfunction (19). Consistent with these findings, it has been reported that increased endogenous myocardial Rac/NADPH oxidase activity in aging rats causes cardiomyocyte hypertrophy and cardiac remodeling (57).…”

“…Recently, we have demonstrated that cardiac-specific transgenic overexpression of a constitutively active mutant form of Zea maize Rac D (ZmRacD) gene resulted in increased myocardial Rac-GTPase activity and reactive oxygen species (ROS) generation in the transgenic mice (TG) of all ages (19). Aging caused markedly higher levels of myocardial Rac expression and Rac-GTPase activity in ZmRacD transgenic mice (19).…”

“…Aging caused markedly higher levels of myocardial Rac expression and Rac-GTPase activity in ZmRacD transgenic mice (19). Importantly, while normal at young age, with aging these TG mice develop a distinct cardiac phenotype manifested by cardiac hypertrophy, relative ventricular chamber dilation, and moderate systolic dysfunction (19).…”

“…Mice. Details regarding the generation and characterization of ZmRacD transgenic (TG) mice have been described previously (19). Briefly, the ␣MHC-RacD transgene was constructed using the cDNA of a constitutively active mutant of ZmRacD gene (28) and ␣-MHC promoter was used to induce selective overexpression of ZmRacD in myocytes of FVB/N wild-type (WT) mice.…”