Mathematical modeling physiological effects of the overexpression of beta(2)-adrenoceptors in mouse ventricular myocytes

作者：Rozier Kelvin; Bondarenko Vladimir E.^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2018, 314(3): H643-H658.

DOI：10.1152/ajpheart.00160.2017

• beta(2)-adrenergic receptors
• calcium transient
• cardiac action potential
• transgenic mice
• zinterol

Transgenic (TG) mice overexpressing beta(2)-adrenergic receptors (beta(2)-ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing beta(2)-ARs. We found that most of the beta(2)-ARs are active in control conditions in TG mice. The simulations describe the dynamics of major signaling molecules in different subcellular compartments, increased basal adenylyl cyclase activity, modifications of action potential shape and duration, and the effects on L-type Ca2+ current and intracellular Ca2+ concentration ([Ca2+](i)) transients upon stimulation of beta(2)-ARs in control, after the application of pertussis toxin, upon stimulation with a specific beta(2)-AR agonist zinterol, and upon stimulation with zinterol in the presence of pertussis toxin. The model also describes the effects of the beta(2)-AR inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca2+](i) transients. The simulation results were compared with experimental data obtained in ventricular myocytes from TG mice overexpressing beta(2)-ARs and with simulation data on wild-type mice. In conclusion, a new comprehensive mathematical model was developed that describes multiple experimental data on TG mice overexpressing beta(2)-ARs and can be used to test numerous hypotheses. As an example, using the developed model, we proved the hypothesis of the major contribution of L-type Ca2+ current to the changes in the action potential and [Ca2+](i) transient upon stimulation of beta(2)-ARs with zinterol.
NEW & NOTEWORTHY We developed a new mathematical model for transgenic mouse ventricular myocytes overexpressing beta(2)-adrenoceptors that describes the experimental findings in transgenic mice. The model reveals mechanisms of the differential effects of stimulation of beta(2)-adrenoceptors in wild-type and transgenic mice overexpressing beta(2)-adrenoceptors.

• 出版日期2018-3