Changes in the receptor-G protein-adenylyl cyclase system in heart failure from various types of heart muscle disease.
The abnormalities of the receptor-G protein-adenylyl cyclase (RCG) system in failing human myocardium as the result of 1) idiopathic dilated cardiomyopathy (IDC), 2) ischemic dilated cardiomyopathy (ISCDC), and 3) primary pulmonary hypertension (PPH) were investigated. Depending on the etiology of heart failure, abnormalities of the RCG system result from a reduced number of beta 1 receptors, uncoupling of beta 1 or beta 2 receptors, alteration of G protein function, or decreased catalytic subunit activity of adenylyl cyclase. Compared to IDC, beta 1 receptor down-regulation is less pronounced in ISCDC, and slightly more pronounced in PPH. Preliminary data suggest that beta 1 receptor down-regulation results from alteration in steady-state receptor mRNA levels. Increased functional activity of Gi protein, which seems to result from posttranslational modification, is observed in IDC and ISCDC. Altered Gi protein function may be the basis for beta-receptor uncoupling in IDC and ISCDC, whereas in PPH, this phenomenon may result from altered adenylyl cyclase function. Catalytic subunit activity of adenylyl cyclase is decreased in order of increasing pulmonary hypertension in right-ventricular preparations from PPH greater than IDC greater than ISCDC. However, catalytic subunit activity is similar in LV preparations from all three groups. The decrease in adenylyl cyclase catalytic subunit activity may be the result of the marked cellular injury produced by pressure overload. In summary, numerous desensitization phenomena occur in the failing human heart that are etiology- or model-dependent. To a certain extent, these changes are teleologically beneficial, as they are able to partially protect the failing heart from potentially toxic adrenergic stimuli.
Bristow
M R
MR
Division of Cardiology, University of Colorado School of Medicine, Denver.
Feldman
A M
AM
D000262:Adenylyl Cyclases / Q000378:metabolism*; D009202:Cardiomyopathies / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases