Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.

TY - JOUR

T1 - Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.

AU - El-Armouche, Ali

AU - Wittköpper, Katrin

AU - Degenhardt, Franziska

AU - Weinberger, Florian

AU - Didié, Michael

AU - Melnychenko, Ivan

AU - Grimm, Michael

AU - Peeck, Micha

AU - Zimmermann, Wolfram-Hubertus

AU - Unsöld, Bernhard

AU - Hasenfuss, Gerd

AU - Dobrev, Dobromir

AU - Eschenhagen, Thomas

PY - 2008

Y1 - 2008

N2 - AIMS: Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. METHODS AND RESULTS: We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection. CONCLUSION: Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.

AB - AIMS: Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. METHODS AND RESULTS: We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection. CONCLUSION: Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.

M3 - SCORING: Zeitschriftenaufsatz

VL - 80

SP - 396

EP - 406

JO - CARDIOVASC RES

JF - CARDIOVASC RES

SN - 0008-6363

IS - 3

M1 - 3

ER -