Expression of adenylyl cyclase and G-protein beta subunit in end-stage human heart failure.
BACKGROUND
One of the abnormalities in end-stage human heart failure is desensitization of the beta-adrenergic signaling pathway, resulting in decreased adenylyl cyclase activity and cyclic adenosine 3',5'-monophosphate formation. This process includes changes in expression of receptors and G-protein alpha subunits. It was hypothesized that changes in the gene expression of G-protein beta subunits (Gbeta) and of adenylyl cyclase itself may contribute to the attenuation of activation of adenylyl cyclase.


RESULTS
The hypothesis was tested by determining messenger RNA steady-state levels (Northern and slot-blot analyses) of adenylyl cyclase type V (a major isoform in adult myocardium) and Gbeta in the left ventricles of patients with terminal heart failure because of idiopathic dilated cardiomyopathy (n = 10) or ischemic heart disease (n = 7) and in the left ventricles of nonfailing donors (n = 5). Adenylyl cyclase type V messenger RNA was elevated by 85 +/- 25% in dilated cardiomyopathy and by 113 +/- 35% in ischemic heart disease (P < .05 vs nonfailing hearts). In contrast, Gbeta messenger RNA was unchanged in cardiomyopathy (3.48 +/- 0.18 pg/microgram total RNA vs nonfailing hearts 3.99 +/- 0.46) and decreased in ischemic heart disease (2.43 +/- 0.26, P < .01).


CONCLUSIONS
The data indicate that gene expression of the major cardiac isoform of adenylyl cyclase (type V) seems increased in human end-stage heart failure. Therefore, attenuated adenylyl cyclase activity in this condition may not be the result of adenylyl cyclase messenger RNA downregulation. Similarly, the unchanged or decreased expression of Gbeta argues against changes in Gbeta contributing to this process.
Holmer
S R
SR
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Germany.
Eschenhagen
T
T
Nose
M
M
Riegger
G A
GA
D000262:Adenylyl Cyclases / Q000032:analysis / Q000378:metabolism*; D000328:Adult; D000704:Analysis of Variance; D015152:Blotting, Northern; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000473:pathology; D019204:GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism*
D007527:Isoenzymes; D012333:RNA, Messenger; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases