role of er stress in ventricular contractile dysfunction in type 2 diabeteser应激的作用在2型糖尿病患者的心室收缩功能障碍.pdfVIP

Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes 1 1 1,2 1 1 1 Akifumi Takada , Takayuki Miki , Atsushi Kuno , Hidemichi Kouzu , Daisuke Sunaga , Takahito Itoh , 1 1 1,3 1 1 Masaya Tanno , Toshiyuki Yano , Tatsuya Sato , Satoko Ishikawa , Tetsuji Miura * 1 Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan, 2 Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan, 3 Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan Abstract Background: Diabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM). Methodology and Principal Findings: In hearts of OLETF, a rat model of T2DM, at 25,30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.965.2 vs. 20.265.6 mmHg/ml), whereas LV end-systolic elastance and positive inotropic responses to b-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyri