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

Abstract

Although 1 -adrenoceptor ( 1 -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 1 -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 1 -AR density as well as isoproterenol-induced increases in cardiac function, intracellular -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 1 -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 1 -AR signal transduction pathway. These observations provide evidence that 1 -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 1 -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.

Behavior of Hypertrophied Right Ventricle during the Development of Left Ventricular Failure Due to Myocardial Infarction

“…Earlier, we reviewed the status of β 1 -adrenoreceptor signal transduction pathway in cardiac hypertrophy and heart failure due to pressure overload and volume overload and reported upregulation in adaptive (physiological) hypertrophy and downregulation of these mechanisms in pathological (maladaptive) hypertrophy or failing hearts [ 8 , 10 ]. We have also carried out studies showing the downregulation of adrenoreceptor mechanisms in the failing left ventricle both at moderate and late stages of heart failure subsequent to myocardial infarction [ 31 , 32 , 46 ].…”

“…The loss of cardiac tissue due to infarct formation is known to produce depression in cardiac output immediately and activate both the sympathetic nervous system and renin-angiotensin system mainly [ 10 , 30 ]. The activation of these neurohormonal systems results in elevated levels of catecholamines and angiotensin II in the circulation for the maintenance of cardiac function.…”

“…These observations indicate differential alterations in the sympathetic nervous system activity of both the right and left ventricles of the infarcted animals. Considering the hypertrophic response of the heart to catecholamines as well as their adaptive and maladaptive effects on the signal transduction and subcellular mechanisms [ 10 , 30 , 31 , 32 , 36 , 46 , 54 ], it is suggested that the observed alterations in behavior of the right ventricle due to myocardial infarction may be a consequence of increased sympathetic activity as well as changes in both plasma levels and cardiac levels of catecholamines.…”

“…Although the muscle mass is increased in both cardiac hypertrophy and heart failure stages, the ventricular function and cardiac output are depressed in heart failure, whereas ventricular function in the hypertrophied (non-failing) heart is either unchanged or upregulated. Likewise, the upregulation and downregulation of cardiac metabolism, Ca 2+ handling by cardiomyocytes, diverse signal transduction pathways and adrenoreceptor-associated responses have been observed at early stages of cardiac hypertrophy and at heart failure stages [ 1 , 3 , 6 , 7 , 8 , 9 , 10 ]. It should be mentioned that cardiac hypertrophy at early stages is compensatory or adaptive in nature and is termed as physiological hypertrophy, whereas at later stages, it is termed as pathological hypertrophy, which is considered a risk factor for the development of heart failure [ 11 ].…”

“…Particularly, alterations in the right ventricle will be described with respect to cardiac hypertrophy and associated signal transduction mechanisms, as well as cardiac function and associated sarcoplasmic reticulum and myofibrillar activities. Because of the derangement of β-adrenoreceptor-associated mechanisms in heart failure [ 10 , 30 ], the existing information for changes in β-adrenoreceptors, adenylyl cyclase and G proteins in the right ventricle will be reviewed. In addition, the role of sympathetic activation in the development of alterations in the right ventricle will be discussed.…”