Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Transgenic Animal Models

Background:

• The serine-threonine kinase, Akt, is known to acutely inhibit cardiomyocyte apoptosis.
• The long-term consequences of chronic Akt activation in the heart remain largely unexplored.

Purpose of the Study:

• To investigate the effects of chronic, cardiac-specific activation of Akt on heart function and structure.
• To determine the impact of sustained Akt signaling on cardiac hypertrophy, cell size, and susceptibility to injury.

Main Methods:

• Generation of transgenic mice with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt).
• Assessment of cardiac phenotype, including heart/body weight ratio, myocyte surface area, and echocardiography.
• Evaluation of infarct size following ischemia-reperfusion injury.

Main Results:

• Transgenic mice exhibited cardiac-specific Akt activation and varying degrees of cardiac hypertrophy.
• Significant increases in heart/body weight ratio and myocyte surface area were observed in transgenic lines.
• Transgenic hearts showed preserved systolic function, reduced infarct size after ischemia-reperfusion, and a spectrum of outcomes including sudden death with cardiac dilatation.

Conclusions:

• Chronic Akt activation is sufficient to induce cardiac hypertrophy and provide cardioprotection against ischemia-reperfusion injury.
• Sustained Akt signaling can lead to a range of cardiac phenotypes, from hypertrophy with preserved function to fatal cardiac dilatation.
• These findings highlight the complex role of Akt in cardiac physiology and pathology.