Mechanisms Underlying Angiotensin II Type 1 Receptor Mediated Electrical Remodeling in Left Ventricular Myocytes
The angiotensin II type 1 (AT1) receptor is a G protein coupled receptor that is highly active in various cardiac disease states. Both the AT1 receptor and its primary effector, angiotensin II (A2), are known to be expressed in cardiac tissue. AT1 receptor activation leads to the transactivation of various intracellular signaling pathways that are known to be responsible for physiological and pathological changes in both cardiac structure and function. In particular, AT1 receptors are involved in physiological adaptation to increased hemodynamic load, but they are also involved in the development of pathological cardiac hypertrophy, which is characterized by structural and electrical remodeling during the progression into heart failure. However, the AT1 receptor-mediated mechanisms underlying these changes are unclear. Therefore, the overall aim of this study was to highlight the importance of AT1 receptors in mechanical stress-induced electrical remodeling and to understand the mechanisms underlying AT1 receptor-mediated regulation.
The following is a summary of our findings. Using the whole-cell patch clamp technique on isolated left ventricular myocytes from a pressure overload-induced mouse model of cardiac hypertrophy, we measured the time dependence of reductions in two predominant repolarizing currents, the fast and slow components of the transient outward K+-current (Ito,fast and IK,slow). These reductions preceded structural remodeling of the heart. We also present evidence supporting our hypothesis that AT1 receptors mediate these reductions. Moreover, we present evidence supporting a novel hypothesis that AT1 receptor-mediated downregulation of Ito,fast and IK,slow does not involve G protein stimulation; rather, it appears to depend on receptor internalization, which leads to reductions in functional Ito,fast and IK,slow channel densities. Finally, with the aid of a computational action potential model and multivariable linear regression, we quantified the relative significance of various electrophysiological parameters, including Ito,fast and IK,slow properties, on the determination of the action potential morphology.
The results presented in this work provide new insights into AT1 receptor-mediated changes that are typically associated with heart failure.