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

Abstract

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.

• Authors: 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
• Journal: Circulation research (Circ Res) Vol. 106 Issue 1 Pg. 129-32 (Jan 08 2010) ISSN: 1524-4571 [Electronic] United States
• PMID: 19910577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Immunosuppressive Agents
• Receptor, Angiotensin, Type 1
• Receptors, Opioid, delta
• Tetrazoles
• Erythropoietin
• Enkephalin, Leucine-2-Alanine
• Valsartan
• Phosphatidylinositol 3-Kinases
• Jak2 protein, rat
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt
• Calcineurin
• Valine
• Losartan
• Tacrolimus

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• 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)
• Male
• Myocardial Reperfusion Injury (metabolism)
• Myocardium (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Inbred OLETF
• Receptor, Angiotensin, Type 1 (agonists, metabolism)
• Receptors, Opioid, delta (agonists, antagonists & inhibitors)
• Signal Transduction
• Species Specificity
• Tacrolimus (pharmacology)
• Tetrazoles (pharmacology)
• Up-Regulation
• Valine (analogs & derivatives, pharmacology)
• Valsartan