Angiotensin II Type 1 Receptor-Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts

被引:57
作者
Hotta, Hiroyuki
Miura, Tetsuji [1 ]
Miki, Takayuki
Togashi, Nobuhiko
Maeda, Takuto
Kim, Seok Jai [2 ]
Tanno, Masaya
Yano, Toshiyuki
Kuno, Atsushi
Itoh, Takahito
Satoh, Takahiro
Terashima, Yoshiaki
Ishikawa, Satoko
Shimamoto, Kazuaki
机构
[1] Sapporo Med Univ, Sch Med, Dept Internal Med 2, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
[2] Chonnam Natl Univ, Sch Med, Dept Anesthesiol & Pain Med, Kwangju, South Korea
关键词
diabetes mellitus; calcineurin; signal transduction; infarct size; PHOSPHORYLATION; INSULIN; MECHANISMS; BLOCKADE; KINASES; PATHWAY; SIZE; AKT;
D O I
10.1161/CIRCRESAHA.109.205385
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.)
引用
收藏
页码:129 / U260
页数:19
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