Long-term beta-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart.
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Long-term beta-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart. / El-Armouche, Ali; Gocht, Fabian; Jaeckel, Elmar; Wittköpper, Katrin; Peeck, Micha; Eschenhagen, Thomas.
In: EUR J HEART FAIL, Vol. 9, No. 11, 11, 2007, p. 1077-1080.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Long-term beta-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart.
AU - El-Armouche, Ali
AU - Gocht, Fabian
AU - Jaeckel, Elmar
AU - Wittköpper, Katrin
AU - Peeck, Micha
AU - Eschenhagen, Thomas
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 9
SP - 1077
EP - 1080
JO - EUR J HEART FAIL
JF - EUR J HEART FAIL
SN - 1388-9842
IS - 11
M1 - 11
ER -
