Novel signalling cascade for cardiac hypertrophy activation by uncoupling and internalization of  1-adrenoceptors

This editorial refers to ‘Endocytosis machinery is required for b1-adrenergic receptor-induced hypertrophy in neonatal rat cardiac myocytes’ by Carmine Morisco et al. ,11 pp. 36–44, this issue. The immediate adaptation of cardiac pump function to haemodynamic stress is achieved by cardiac functional response, such as an increase in heart rate and cardiac contractility regulated through the Frank-Starling mechanism, the force-frequency relationship and adrenergic nerve stimulation. When the haemodynamic stress continues, cardiac hypertrophy develops first as the adaptive response of the myocardium that progresses to pathological (maladaptive) hypertrophy associated with fibrosis and apoptosis, and ultimately to heart failure. Maladaptive cardiac hypertrophy generally predisposes to heart failure and is an important risk factor for an increase in death of patients with heart failure, and therefore the signalling processes responsible for the development of cardiac hypertrophy have been and will be an important research target for therapies based on an understanding of the pathophysiology and development of heart failure. During the course of cardiac hypertrophy caused by long-lasting pressure and volume overload, and after myocardial infarction, various neurohumoral factors, including catecholamines, angiotensin II (Ang II), endothelin-1 (ET-1), and cytokines, are released into the circulation to advance and/or modulate the course of cardiac hypertrophy.1,2 Activation of various protein kinases is involved in the induction of cardiac hypertrophy.3 For example, membrane receptors of Ang II (AT1 receptor), ET-1 and phenylephrine (PE; α1-adrenoceptor: α1-AR) belong to the same family and are coupled to heterotrimeric GTP binding proteins, Gq/11, resulting in the generation of 1,2-diacylglycerol (DAG) which activates protein kinase C and leads to cardiac hypertrophy. Overexpression of DAG kinase ζ, which converts DAG to inactive metabolites, suppresses the hypertrophy … * Corresponding author. Tel: +81 23 628 5234; fax: +81 236 28 5235. E-mail address : mendou{at}med.id.yamagata-u.ac.jp