Document Detail

Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts.
MedLine Citation:
PMID:  19910577     Owner:  NLM     Status:  MEDLINE    
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 (AT1) 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 AT1 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 AT1 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 AT1 receptor-mediated upregulation of calcineurin activity.
Hiroyuki Hotta; Tetsuji Miura; Takayuki Miki; Nobuhiko Togashi; Takuto Maeda; Seok Jai Kim; Masaya Tanno; Toshiyuki Yano; Atsushi Kuno; Takahito Itoh; Takahiro Satoh; Yoshiaki Terashima; Satoko Ishikawa; Kazuaki Shimamoto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-11-12
Journal Detail:
Title:  Circulation research     Volume:  106     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-08     Completed Date:  2010-01-22     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  129-32     Citation Subset:  IM    
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
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MeSH Terms
Angiotensin II Type 1 Receptor Blockers / pharmacology
Calcineurin / metabolism*
Diabetes Mellitus, Type 2 / metabolism*
Enkephalin, Leucine-2-Alanine / metabolism
Erythropoietin / pharmacology
Immunosuppressive Agents / pharmacology
Ischemic Preconditioning, Myocardial
Janus Kinase 2 / metabolism
Losartan / pharmacology
Myocardial Reperfusion Injury / metabolism
Myocardium / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
Rats, Inbred OLETF
Receptor, Angiotensin, Type 1 / agonists,  metabolism*
Receptors, Opioid, delta / agonists,  antagonists & inhibitors
Signal Transduction*
Species Specificity
Tacrolimus / pharmacology
Tetrazoles / pharmacology
Valine / analogs & derivatives,  pharmacology
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Immunosuppressive Agents; 0/Receptor, Angiotensin, Type 1; 0/Receptors, Opioid, delta; 0/Tetrazoles; 109581-93-3/Tacrolimus; 11096-26-7/Erythropoietin; 114798-26-4/Losartan; 137862-53-4/valsartan; 63631-40-3/Enkephalin, Leucine-2-Alanine; 7004-03-7/Valine; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Kinase 2; EC protein, rat; EC Proteins c-akt; EC

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