Short Communication: Angiotensin II Type 1 Receptor–Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts
| Autor: | Seok Jai Kim, Takahiro Satoh, Satoko Ishikawa, Kazuaki Shimamoto, Masaya Tanno, Tetsuji Miura, Takahito Itoh, Takuto Maeda, Yoshiaki Terashima, Nobuhiko Togashi, Hiroyuki Hotta, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Angiotensin receptor
medicine.medical_specialty Physiology business.industry Phosphatidylinositol 3-Kinases Angiotensin II Calcineurin chemistry.chemical_compound Endocrinology Losartan chemistry Downregulation and upregulation Internal medicine Medicine Ischemic preconditioning Phosphatidylinositol Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | Circulation Research. 106:129-132 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.109.205385 |
| Popis: | 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 δ-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. |
| Databáze: | OpenAIRE |
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