Enhanced cardiac function in transgenic mice expressing a Ca(2+)-stimulated adenylyl cyclase

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Transgenic Animal Models

Background:

• Endogenous cardiac adenylyl cyclases (AC) are inhibited by micromolar calcium (Ca2+).
• Beta-adrenergic receptor stimulation normally activates cardiac AC, but this is counteracted by Ca2+ inhibition.

Purpose of the Study:

• To investigate the role of Ca2+-stimulatable AC8 in cardiac function.
• To generate a novel transgenic mouse model for studying cardiac cAMP and Ca2+ signaling.

Main Methods:

• Generation of transgenic mice expressing cardiac-specific AC8.
• Measurement of AC activity in heart membranes.
• Assessment of in vivo protein kinase A (PKA) activity.
• Noninvasive echocardiography to evaluate cardiac function.

Main Results:

• AC activity increased >7-fold in AC8 transgenic mouse hearts, stimulated by Ca2+.
• Basal PKA activity was elevated 4-fold in vivo.
• Cardiac function, heart rate, and contractility were unchanged under basal conditions.
• Enhanced intrinsic contractility observed upon parasympathetic tone release, with unresponsiveness to further beta-adrenergic stimulation.

Conclusions:

• Cardiac-specific overexpression of AC8 enhances cAMP signaling and cardiac contractility.
• AC8 transgenic mice provide a unique model to dissect Ca2+ and cAMP interplay in the heart.
• AC8 expression does not impair basal cardiac performance, suggesting potential therapeutic applications.