Long-term β-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart

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• 作者：Ali El-Armouche ; Fabian Gocht ; Elmar Jaeckel ; Katrin Wittkö ; pper ; Micha Peeck ; Thomas Eschenhagen
• 关键词：Phosphatase inhibitor-1 ; Phospholamban ; Beta-adrenergic signalling
• 刊名：European Journal of Heart Failure
• 出版年：2007
• 出版时间：November 2007
• 年：2007
• 卷：9
• 期：11
• 页码：1077-1080
• 全文大小：273 K

文摘

Desensitization of the β-adrenoceptor/cAMP/PKA pathway is a hallmark of heart failure. Inhibitor-1 (I-1) acts as a conditional amplifier of β-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 β-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 40 % and abolished the inotropic response to acute ISO in papillary muscles by 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 β-adrenergic signalling cascade.