β-Adrenergic signal transduction in the failing and hypertrophied myocardium

Abstract

 A strong sympathetic activation has been observed in heart failure and is the cause of β-adrenergic desensitization in this condition. On the receptor level there is downregulation of β₁-adrenergic receptors and uncoupling of β₂-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of β-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. β₃-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein α subunits (Giα) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein α and βγ subunits, have been observed to be unchanged. Recent evidence shows that increases in Giα also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Giα can suppress adenylyl cyclase in the absence of β-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Giα may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.