title: Left ventricular pressure-volume measurements and myocardial gene expression profile in type 2 diabetic Goto-Kakizaki rats.
abstract: The Goto-Kakizaki (GK) rat, a non-obese model of type 2 diabetes mellitus (T2DM), was generated by the selective inbreeding of glucose-intolerant Wistar rats. This is a convenient model for studying diabetes-induced cardiomyopathy independently from the effects of the metabolic syndrome. We investigated the myocardial functional and structural changes and underlying molecular pathomechanisms of short-term and mild T2DM. The presence of DM was confirmed by an impaired oral glucose tolerance in the GK rats compared with the age-matched nondiabetic Wistar rats. Data from cardiac catheterization showed that in GK rats, although the systolic indexes were not altered, the diastolic stiffness was increased compared with nondiabetics (end-diastolic-pressure-volume-relationship: 0.12 ± 0.04 vs. 0.05 ± 0.01 mmHg/μl, P < 0.05). Additionally, DM was associated with left-ventricular hypertrophy and histological evidence of increased myocardial fibrosis. The plasma pro-B-type natriuretic peptide, the cardiac troponin-T, glucose, and the urinary glucose concentrations were significantly higher in GK rats. Among the 125 genes surveyed using PCR arrays, DM significantly altered the expression of five genes [upregulation of natriuretic peptide precursor-A and connective tissue growth factor, downregulation of c-reactive protein, interleukin-1β, and tumor necrosis factor (TNF)-α mRNA-level]. Of the altered genes, which were evaluated by Western blot, only TNF-α protein expression was significantly decreased. The ECG recordings revealed no significant differences. In conclusion, while systolic dysfunction, myocardial inflammation, and abnormal electrical conduction remain absent, short-term and mild T2DM induce the alteration of cardiac TNF-α at both the mRNA and protein levels. Further assessments are required to reveal if TNF-α plays a role in the early stage of diabetic cardiomyopathy development.
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany; korkmaz@uni-heidelberg.de.
authors: Sevil
authors: S
authors: Korkmaz-Icöz
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Alice
authors: A
authors: Lehner
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Shiliang
authors: S
authors: Li
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Adrian
authors: A
authors: Vater
authors: Heart and Vascular Center, Semmelweis University, Budapest, Hungary; and.
authors: Tamás
authors: T
authors: Radovits
authors: Department of Internal Medicine I, University of Heidelberg, Heidelberg, Germany.
authors: Maik
authors: M
authors: Brune
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany; Heart and Vascular Center, Semmelweis University, Budapest, Hungary; and.
authors: Mihály
authors: M
authors: Ruppert
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Xiaoxin
authors: X
authors: Sun
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Paige
authors: P
authors: Brlecic
authors: Department of Internal Medicine I, University of Heidelberg, Heidelberg, Germany.
authors: Markus
authors: M
authors: Zorn
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Matthias
authors: M
authors: Karck
authors: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors: Gábor
authors: G
authors: Szabó
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation; D004452:Echocardiography; D004562:Electrocardiography; D005355:Fibrosis; D005951:Glucose Tolerance Test; D006029:Glycosuria; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D020107:Troponin T / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D001786:Blood Glucose; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D010446:Peptide Fragments; D012333:RNA, Messenger; D020107:Troponin T; D014409:Tumor Necrosis Factor-alpha; C472610:atrial natriuretic peptide, rat; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D055513:Connective Tissue Growth Factor; C002744:3-nitrotyrosine; D014443:Tyrosine; D009320:Atrial Natriuretic Factor; D002097:C-Reactive Protein
keywords: Goto-Kakizaki rats; cardiac function; diabetic cardiomyopathy; gene expression profiling; type 2 diabetes mellitus