Molecular aspects of adrenergic signal transduction in cardiac failure.
Abnormal beta-adrenergic signal transduction and intracellular Ca2+ handling appear to be a major cause of systolic and diastolic dysfunction in humans with heart failure. The precise mechanisms which cause an alteration in Ca2+ handling have been a subject of investigation in recent years. Several lines of evidence suggest that activation of neurohormonal systems plays a central role. Altered Ca2+-handling (increased diastolic concentrations, reduced systolic Ca2+ release) have a strong impact on diastolic and systolic performance of failing hearts. Sarcoplasmic reticulum Ca2+ ATPase is reduced in activity and in steady-state mRNA concentration. The Na+-Ca2+ exchanger is upregulated at the mRNA and protein levels. Phospholamban depends strongly on cAMP-dependent phosphorylation. A strong sympathetic activation has been shown to desensitize the cAMP system. At the receptor level, there is downregulation of beta1-adrenergic receptors. An uncoupling of beta2-adrenoceptors has been attributed to an increased activity and gene expression of beta-adrenergic receptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. Finally, recent evidence suggests that cAMP-dependent transcription mechanisms may play a role during beta-adrenergic stimulation and cardiomyopathy with heart failure - by means of altered actions of cAMP response element binding protein, the cAMP response element modulator, or the activating transcription factor 1. The exact characterization of signal transduction defects could offer novel approaches to the pharmacological treatment of heart failure.
Hajjar
R J
RJ
Harvard Medical School, Massachusetts General Hospital, Cardiovascular Center, Charlestown 02129-2060, USA.
Müller
F U
FU
Schmitz
W
W
Schnabel
P
P
Böhm
M
M
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006331:Heart Diseases; D006801:Humans; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D015398:Signal Transduction
D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000252:Calcium-Transporting ATPases