Status of β1-Adrenoceptor Signal Transduction System in Cardiac Hypertrophy and Heart Failure

Abstract

Although β1-adrenoceptor (β1-AR) signal transduction, which maintains cardiac function, is downregulated in failing hearts, the mechanisms for such a defect in heart failure are not fully understood. Since cardiac hypertrophy is invariably associated with heart failure, it is possible that the loss of β1-AR mechanisms in failing heart occurs due to hypertrophic process. In this regard, we have reviewed the information from a rat model of adaptive cardiac hypertrophy and maladaptive hypertrophy at 4 and 24 weeks after inducing pressure overload as well as adaptive cardiac hypertrophy and heart failure at 4 and 24 weeks after inducing volume overload, respectively. Varying degrees of alterations in β1-AR density as well as isoproterenol-induced increases in cardiac function, intracellular Ca2+-concentration in cardiomyocytes and adenylyl cyclase activity in crude membranes have been reported under these hypertrophic conditions. Adaptive hypertrophy at 4 weeks of pressure or volume overload showed unaltered or augmented increases in the activities of different components of β1-AR signaling. On the other hand, maladaptive hypertrophy due to pressure overload and heart failure due to volume overload at 24 weeks revealed depressions in the activities of β1-AR signal transduction pathway. These observations provide evidence that β1-AR signal system is either unaltered or upregulated in adaptive cardiac hypertrophy and downregulated in maladaptive cardiac hypertrophy or heart failure. Furthermore, the information presented in this article supports the concept that downregulation of β1-AR mechanisms in heart failure or maladaptive cardiac hypertrophy is not due to hypertrophic process per se. It is suggested that a complex mechanism involving the autonomic imbalance may be of a critical importance in determining differential alterations in non-failing and failing hearts.

Keywords

• adaptive cardiac hypertrophy
• maladaptive cardiac hypertrophy
• heart failure
• β1-adrenoceptors
• intracellular ca2+
• adenylyl cyclase
• cardiac function