Abstract 15147: Increased ER Stress is a Fundamental Mechanism for Impairment of Cardioprotective Signaling in Type 2 Diabetes
Background: Recently, we found two mechanisms that impair cardioprotective signaling in a rat model of obese type 2 diabetes (T2DM), OLETF: up-regulation of calcineurin activity and increased ER stress which disrupts signaling from ERK to glycogen synthase kinase-3β (GSK-3β). Here we tested whether calcineurin and/or ER stress are fundamental mechanisms of defects in protective signaling in diabetic hearts.
Methods: A model of “non-obese” T2DM, Goto-Kakizaki rats (GK), and its non-diabetic control (WKY) underwent 20-min coronary artery occlusion/2-hr reperfusion. Groups of rats were treated with 4-phenylbutyric acid (4-PBA, 40 mg/kg/day) for 7 days to reduce ER stress or with losartan (3 mg/kg/day) for 2 weeks before acute experiments. Using separate groups of rats, mitochondria were isolated from the myocardium after 20-min ischemia/5-min reperfusion, and their calcium retention capacity (CRC) was determined as an index of threshold for opening of the mitochondrial permeability transition pore (mPTP).
Results: Levels of GRP78 and GRP94, markers of ER stress, in the myocardium were increased by 31% and 42%, respectively, in GK compared with those in WKY. In contrast to OLETF, calcineurin activity in GK was not elevated, being similar to that in WKY (0.81±0.05 vs. 0.89±0.10 nmol/mg/min). As in OLETF, injection of erythropoietin (EPO, 5000 IU/kg, i.v.) failed to limit infarct size as % of area at risk (%IS/AR) in GK (52.1±2.7 vs. 55.9±2.6%), though EPO significantly reduced %IS/AR in WKY (45.7±4.4 vs. 62.0±5.7%). EPO induced phosphorylation of ERK and GSK3-β in WKY, whereas only ERK was phosphorylated by EPO in GK. Treatment with 4-PBA restored the GSK-3β phosphorylation and increase in CRC by EPO receptor activation as well as the infarct size-limiting effect of EPO (%IS/AR = 38.4±2.6%) in GK. Losartan reduced myocardial GRP78 level and restored protection by EPO in GK (%IS/AR = 36.0±4.2 vs. 51.1±5.5).
Conclusion: In T2DM, increased ER stress by activation of the angiotensin II type 1 receptor is a primary mechanism impairing cardioprotective signaling that inhibits mPTP opening via GSK-3β phosphorylation. Defects in protective signaling by increased calcineurin activity may be specific to obese T2DM.
- © 2010 by American Heart Association, Inc.