El-Armouche Ali, Wittköpper Katrin, Degenhardt Franziska, Weinberger Florian, Didié Michael, Melnychenko Ivan, Grimm Michael, Peeck Micha, Zimmermann Wolfram H, Unsöld Bernhard, Hasenfuss Gerd, Dobrev Dobromir, Eschenhagen Thomas
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Cardiovasc Res. 2008 Dec 1;80(3):396-406. doi: 10.1093/cvr/cvn208. Epub 2008 Aug 8.
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.
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.
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.
磷酸酶抑制剂 -1（I-1）是蛋白激酶 A 下游β - 肾上腺素能信号的条件放大器，仅在其蛋白激酶 A 磷酸化形式下抑制 1 型磷酸酶。I-1 在衰竭心脏中表达下调，从而导致β - 肾上腺素能脱敏。目前尚不清楚这应被视为主要是不利反应还是保护反应。
我们构建了心脏特异性过表达 I-1 的转基因小鼠（I-1-TG），并评估了 I-1 基因靶向敲除小鼠（I-1-KO）的心脏功能以及对儿茶酚胺的反应。将两组与它们的野生型（WT）同窝小鼠进行比较。I-1-TG 出现心脏肥大和轻度功能障碍，同时伴有 PP1 丰度和活性的显著代偿性增加，这混淆了因果关系。I-1-KO 的心脏结构正常，敏感性略有降低，但在体外和体内对β - 肾上腺素能刺激的最大收缩反应未改变。值得注意的是，I-1-KO 对致死性儿茶酚胺诱导的心律失常以及由β - 肾上腺素能激动剂异丙肾上腺素 7 天输注诱导的肥大和扩张具有部分保护作用。此外，I-1-KO 在慢性异丙肾上腺素处理后表现出部分保留的急性β - 肾上腺素能反应，而在同样处理的 WT 小鼠中则完全没有。在分子水平上，I-1-KO 显示心脏兰尼碱受体/Ca(2+)释放通道以及肌浆网（SR）Ca(2+)-ATP 酶调节蛋白受磷蛋白的稳态磷酸化水平较低。这些改变可能降低舒张期 Ca(2+)释放和 Ca(2+)摄取的倾向，从而稳定肌浆网并解释了这种保护作用。
综上所述，I-1 的缺失减轻了儿茶酚胺对心脏的有害影响，提示心力衰竭时 I-1 的下调是一种有益的脱敏机制，抑制 I-1 是心力衰竭治疗的一种潜在新策略。
