Abstract 445: Phosphatase Inhibitor-1 is Critically Involved in Acute and Chronic Catecholamine Stress Responses
Desensitization of the β-adrenoceptor/cAMP/PKA system is a hallmark of heart failure. The PKA-phosphorylated inhibitor-1 (I-1) amplifies β-adrenergic signaling via inhibition of type-1 phosphatases. I-1 is markedly downregulated in failing human hearts. To test whether this is a consequence of the excessive adrenergic drive in heart failure, rats were treated via minipumps with 2.4 mg/kgxd isoprenaline (ISO, n=7) or 0.9% NaCl (n=8) for 4 d. In ISO-treated rats, heart-to-body weight ratio (HW/BW) increased by 28±3% and I-1 protein levels were downregulated by 61±29%. To address whether a decrease in I-1 protects from or aggravates cardiac remodeling we evaluated mice with targeted disruption of the I-1 gene (KO). KO were phenotypically normal (HW/BW 4.8±0.1 vs. 4.7±0.1 mg/g in WT, n=16), but showed a rightward shift of the ISO concentration-response curve in isolated left atria preparations (EC50 40.9 vs. 23.9 nM, n=12). This observation was compatible with the proposed amplifier role of I-1 and suggested that the loss of I-1 could be beneficial under conditions of increased catecholamine stimulation. KO and WT littermates were therefore treated with ISO (15 mg/kgxd for 7 d) or 0.9% NaCl. In WT, ISO induced cardiac hypertrophy as indicated by increased HW/BW (+17±2%, n=19), cardiomyocyte cross sectional area (CCSA, +32±2%, n=4) and echocardiographically determined left ventricular mass (LVM, +39±4%, n=13). In KO, the hypertrophic response was significantly attenuated for all parameters (HW/BW, +11±2%; CCSA, +19±2%; LVM: +20±5%). In addition, chronic ISO-exposure induced complete desensitization to acute β-adrenergic stimulation in WT (dobutamine-induced increase in FAS: +1±3% [n=12] after chronic ISO vs. +54±5% after NaCl [n=10]). In contrast, the positive inotropic response to dobutamine was partly preserved in KO (FAS: +20±5% [n=6] after chronic ISO vs. +51±5% after NaCl [n=8]). In summary,
I-1 downregulation in heart failure is a consequence of excessive adrenergic drive and
I-1 deficiency attenuates ISO-induced cardiac hypertrophy and β-adrenergic desensitization.
This suggests that I-1 downregulation in heart failure is a protective mechanism. Thus, I-1 suppression may be a promising strategy in the therapy of heart failure.