Role of G-proteins in altered beta-adrenergic responsiveness in the failing and hypertrophied myocardium.
In the heart and other tissues, beta-adrenergic desensitization occurs during treatment with catecholamines. In heart failure, a strong sympathetic activation has been observed and is the cause of beta-adrenergic desensitization in this condition. On the receptor level, there is a downregulation of beta 1-adrenergic receptors as well as an uncoupling of beta 2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-ARK2 in failing myocardium leading to phosphorylation and uncoupling of receptors. In addition, an increase of inhibitory G-protein alpha-subunits (Gi alpha) 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 alpha-subunits and beta gamma-subunits have been observed to be unchanged. Recently, evidence has been raised that increases of Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy in monogenic and polygenic as well as in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure these observations indicate that adenylyl cyclase desensitization by Gi alpha could be a pathophysiologically relevant mechanism to contribute to the progression from compensated cardiac hypertrophy to heart failure.
Böhm
M
M
Klinik III für Innere Medizin Universität Köln, Germany.
Flesch
M
M
Schnabel
P
P
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D018450:Disease Progression; D019204:GTP-Binding Proteins / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D009200:Myocardial Contraction; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D019204:GTP-Binding Proteins