Interactions between phospholamban and beta-adrenergic drive may lead to cardiomyopathy and early mortality.
BACKGROUND
Relieving the inhibition of sarcoplasmic reticular function by phospholamban is a major target of beta-adrenergic stimulation. Chronic beta-adrenergic receptor activity has been suggested to be detrimental, on the basis of transgenic overexpression of the receptor or its signaling effectors. However, it is not known whether physiological levels of sympathetic tone, in the absence of preexisting heart failure, are similarly detrimental.


RESULTS
Transgenic mice overexpressing phospholamban at 4-fold normal levels were generated, and at 3 months, they exhibited mildly depressed ventricular contractility without heart failure. As expected, transgenic cardiomyocyte mechanics and calcium kinetics were depressed, but isoproterenol reversed the inhibitory effects of phospholamban on these parameters. In vivo cardiac function was substantially depressed by propranolol administration, suggesting enhanced sympathetic tone. Indeed, plasma norepinephrine levels and the phosphorylation status of phospholamban were elevated, reflecting increased adrenergic drive in transgenic hearts. On aging, the chronic enhancement of adrenergic tone was associated with a desensitization of adenylyl cyclase (which intensified the inhibitory effects of phospholamban), the development of overt heart failure, and a premature mortality.


CONCLUSIONS
The unique interaction between phospholamban and increased adrenergic drive, elucidated herein, provides the first evidence that compensatory increases in catecholamine stimulation can, even in the absence of preexisting heart failure, be a primary causative factor in the development of cardiomyopathy and early mortality.
Dash
R
R
Department of Cardiovascular Biology, Millennium Pharmaceuticals Inc, Cambridge, Massachusetts, USA.
Kadambi
V
V
Schmidt
A G
AG
Tepe
N M
NM
Biniakiewicz
D
D
Gerst
M J
MJ
Canning
A M
AM
Abraham
W T
WT
Hoit
B D
BD
Liggett
S B
SB
Lorenz
J N
JN
Dorn
G W
GW
Kranias
E G
EG
D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009202:Cardiomyopathies / Q000097:blood / Q000209:etiology* / Q000401:mortality; D004452:Echocardiography; D006333:Heart Failure / Q000209:etiology / Q000401:mortality; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D010766:Phosphorylation; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D016277:Ventricular Function, Left; D000099211:Phospholamban
D000262:Adenylyl Cyclases; D000319:Adrenergic beta-Antagonists; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D009638:Norepinephrine; D011433:Propranolol; D011943:Receptors, Adrenergic, beta; D000099211:Phospholamban