Angiotensin II Type 1 Receptor-Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts
Angiotensin II Type 1 Receptor-Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts
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DOI：
10.1161/circresaha.109.205385
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发表时间：
2010-01-08
影响因子：
20.1
通讯作者：
Shimamoto, Kazuaki
中科院分区：
文献类型：
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作者：
Hotta, Hiroyuki;Miura, Tetsuji;Shimamoto, Kazuaki
理由：糖尿病心脏对缺血预处理具有抵抗性，因为糖尿病相关的磷脂酰肌醇3-激酶(PI3K)-Akt信号通路受损。糖尿病损害PI3K-Akt信号的机制尚不清楚。目的：在这里，我们检验了糖尿病心脏中PI3K上游Jak2磷酸化通过血管紧张素II型1 （AT(1)）受体介导的机制受损的假设。方法和结果：2型糖尿病大鼠模型（Otsuka-Long-Evans-Tokushima fatty [OLETF]大鼠）在缺血20分钟/2小时再灌注后的梗死面积（作为危险区域的百分比）大于对照组（Long-Evans-Tokushima-Otsuka [LETO]大鼠）（60.4 +/- 1.6% vs 48.4 +/- 1.3%）。促红细胞生成素或DADLE （[D-Ala2， D-Leu5]-脑啡肽醋酸酯）（一种阿片受体激动剂）激活jak2介导的信号，在LETO大鼠中限制梗死面积（27.7 +/- 3.4%和24.8 +/- 5.0%），但在OLETF大鼠中没有（53.9 +/- 5.3%和55.0 +/- 2.2%）。缬沙坦或氯沙坦阻断AT(1)受体2周后，OLETF大鼠对促红细胞生成素诱导的梗死面积限制的心肌反应恢复（39.4 +/- 4.9%和31.2 +/- 7.5）。OLETF大鼠红细胞生成素无法磷酸化Jak2和Akt，钙调磷酸酶活性显著高于LETO大鼠。缬沙坦治疗两周使OLETF大鼠钙调磷酸酶活性正常化，并恢复Jak2对促红细胞生成素的反应。FK506对钙调磷酸酶的抑制可以模拟AT(1)受体阻断的这种作用。结论：这些结果表明，由于AT(1)受体介导的钙调磷酸酶活性上调，糖尿病心脏难以受到jak2激活配体的保护。（Circ Res. 2010;106:129-132。）
Rationale: The diabetic heart is resistant to ischemic preconditioning because of diabetes-associated impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. The mechanism by which PI3K-Akt signaling is impaired by diabetes remains unclear.Objective: Here, we examined the hypothesis that phosphorylation of Jak2 upstream of PI3K is impaired in diabetic hearts by an angiotensin II type 1 (AT(1)) receptor-mediated mechanism.Methods and Results: Infarct size (as percentage of risk area) after 20-minute ischemia/2-hour reperfusion was larger in a rat model of type 2 diabetes (Otsuka-Long-Evans-Tokushima fatty [OLETF] rat) than in its control (Long-Evans-Tokushima-Otsuka [LETO] rat) (60.4 +/- 1.6% versus 48.4 +/- 1.3%). Activation of Jak2-mediated signaling by erythropoietin or DADLE ([D-Ala2, D-Leu5]-enkephalin acetate), a delta-opioid receptor agonist, limited infarct size in LETO rats (27.7 +/- 3.4% and 24.8 +/- 5.0%) but not in OLETF rats (53.9 +/- 5.3% and 55.0 +/- 2.2%). Blockade of the AT(1) receptor by valsartan or losartan for 2 weeks restored the myocardial response of OLETF rats to erythropoietin-induced infarct size limitation (39.4 +/- 4.9% and 31.2 +/- 7.5). In OLETF rats, erythropoietin failed to phosphorylate both Jak2 and Akt, and calcineurin activity was significantly higher than in LETO rats. Two-week treatment with valsartan normalized calcineurin activity in OLETF rats and restored the response of Jak2 to erythropoietin. This effect of AT(1) receptor blockade was mimicked by inhibition of calcineurin by FK506.Conclusions: These results suggest that the diabetic heart is refractory to protection by Jak2-activating ligands because of AT(1) receptor-mediated upregulation of calcineurin activity. (Circ Res. 2010;106:129-132.)