Long-term β-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-I (1-1) 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-adrencrgic 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 similar to 40% and abolished the inotropic response to acute ISO in papillary muscles by similar to 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 Ca-45(2+) 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. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.