Short Communication: 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 iabetes mellitus not only accelerates atherosclerosis of the coronary artery but also induces functional and structural abnormalities in the myocardium. In addition, recent studies have shown that myocardial response to ischemic preconditioning (IPC) and its mimetics is blunted or lost in diabetic hearts. 1-3 Protection afforded by IPC is triggered by activation of G protein-coupled receptors 5 and impaired activation of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) in models of diabetes mellitus have been reported. 1-3 Our recent study 3 showed impaired activation of Jak2 and endoplasmic reticulum (ER) stress-mediated disruption of signaling from ERK to glycogen synthase kinase (GSK)-3␤ in diabetic hearts. However, the mechanism by which Jak2-mediated signaling is disabled in diabetic hearts remains unclear. In the present study, we tested the hypothesis that Jak2-mediated protection is impaired in diabetic myocardium by an angiotensin II type 1 (AT 1 ) receptor-mediated mechanism via upregulation of SOCS3 (suppressor of cytokine signaling 3)-Jak2 interaction or calcineurin. MethodsMale Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, which spontaneously develop obesity and type 2 diabetes, and their controls (Long-Evans-Tokushima-Otsuka [LETO] rats) were used. Preparation of myocardial infarction, immunoblotting, quantitative real-time RT-PCR, calcineurin activity assay, and determination of insulin sensitivity were performed by standard methods (see the expanded Methods section in the Online Data Supplement, available at

Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2

“…The plasma glucose level was significantly higher in OLETF rats than in LETO rats (286.4 Ϯ 10.5 vs. 118.2 Ϯ 4.2 mg/dl, P Ͻ 0.05), confirming an obese T2DM phenotype in OLETF rats. The results were consistent with the results of our previous studies (7,17,35) showing hyperinsulinemia, insulin resistance, and hypertriglyceridemia in OLETF rats at the same age.…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…The majority of preclinical experimental studies investigating the effect of diabetes on the myocardial response to either ischemic or pharmacologic preconditioning has found that the presence of diabetes renders the heart more resistant to the infarct size-limiting effects of preconditioning (reviewed in Ferdinandy et al, 2007;Miki et al, 2012). Recent experimental studies have also shown that the cardioprotective efficacy of pharmacologic preconditioning using a variety of different agents, including erythropoietin (Miki et al, 2009;Hotta et al, 2010), d-opioid receptor agonist (Hotta et al, 2010), isoflurane (Matsumoto et al, 2009), L-glutamate (Povlsen et al, 2009), remifentanil , and helium (Huhn et al, 2009b), is also impaired in the diabetic heart. Whittington et al (2013b) investigated the combined effect of diabetes and age on the response of the heart to acute ischemia/ reperfusion injury.…”

“…Miki et al (2009) reported that the presence of augmented endoplasmic reticulum stress in the diabetic heart blocked ERK1/2-mediated phosphorylation of GSK-3b, leading to increased susceptibility to MPTP opening and mitochondrial calcium overload. Hotta et al (2010) showed that the angiotensin II subtype 1 receptormediated upregulation of calcineurin in the diabetic rat heart interfered with the phosphorylation of Janusactivated kinase 2 and PI3K-Akt signaling, thereby affecting the efficacy of pharmacologic preconditioning. Ajmani et al (2011) provided data implicating caveolin, which was increased in the diabetic heart and interfered with endothelial NO synthase (eNOS) activity, contributing to the inability of the diabetic heart to respond to ischemic preconditioning.…”

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease

“…Infarct size experiments were performed as previously reported [16,39]. In brief, rats were anesthetized as described above and ventilated with a Harvard Model 683 respirator (Harvard Apparatus, South Natick, MA, USA).…”