Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts.
BACKGROUND
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.


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.
Hotta
Hiroyuki
H
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Miura
Tetsuji
T
Miki
Takayuki
T
Togashi
Nobuhiko
N
Maeda
Takuto
T
Kim
Seok Jai
SJ
Tanno
Masaya
M
Yano
Toshiyuki
T
Kuno
Atsushi
A
Itoh
Takahito
T
Satoh
Takahiro
T
Terashima
Yoshiaki
Y
Ishikawa
Satoko
S
Shimamoto
Kazuaki
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D053614:Janus Kinase 2 / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013045:Species Specificity; D016559:Tacrolimus / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D007166:Immunosuppressive Agents; D044140:Receptor, Angiotensin, Type 1; D017465:Receptors, Opioid, delta; D013777:Tetrazoles; D004921:Erythropoietin; D016308:Enkephalin, Leucine-2-Alanine; D000068756:Valsartan; D019869:Phosphatidylinositol 3-Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; D014633:Valine; D019808:Losartan; D016559:Tacrolimus