Long-term beta-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart.
Desensitization of the beta-adrenoceptor/cAMP/PKA pathway is a hallmark of heart failure. Inhibitor-1 (I-1) acts as a conditional amplifier of beta-adrenergic signalling downstream of PKA by inhibiting type-1 phosphatases in the PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus presumably contributes to beta-adrenergic desensitization. To test whether I-1 downregulation is a consequence of excessive adrenergic drive in heart failure, rats were treated via minipumps with isoprenaline 2.4 mg/kg/day (ISO) or 0.9% NaCl for 4 days. As expected, chronic ISO increased heart-to-body weight ratio by approximately 40% and abolished the inotropic response to acute ISO in papillary muscles by approximately 50%. In the ISO-treated hearts I-1 mRNA and protein levels were decreased by 30% and 54%, respectively. This was accompanied by decreased phospholamban phosphorylation (-40%), a downstream target of I-1, and a reduction in 45Ca2+ uptake (-54%) in membrane vesicles. Notably, phospholamban phosphorylation correlated significantly with I-1 protein levels indicating a causal relationship. We conclude that I-1 downregulation in heart failure is likely a consequence of the increased sympathetic adrenergic drive and participates in desensitization of the beta-adrenergic signalling cascade.
El-Armouche
Ali
A
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf; Hamburg, Germany. a.el-armouche@uke.uni-hamburg.de
Gocht
Fabian
F
Jaeckel
Elmar
E
Wittköpper
Katrin
K
Peeck
Micha
M
Eschenhagen
Thomas
T
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism; D018709:Statistics, Nonparametric
D000318:Adrenergic beta-Agonists; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; C021042:protein phosphatase inhibitor-1; D007545:Isoproterenol; D002118:Calcium