title: Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients.
abstract: Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction-relaxation cycle and intracellular Ca(2+) regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca(2+) transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and non-diabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca(2+) handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca(2+) handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca(2+) was significantly prolonged, but relaxation of the Ca(2+) transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca(2+) release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca(2+) release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca(2+) release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.
authors.affiliation: Laboratory of Muscle Research and Molecular Cardiology, Department III of Internal Medicine, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany. Hannes.Reuter@koeln.de
authors.forename: Hannes
authors.initials: H
authors.lastname: Reuter
authors.forename: Sabine
authors.initials: S
authors.lastname: Grönke
authors.forename: Christian
authors.initials: C
authors.lastname: Adam
authors.forename: Maida
authors.initials: M
authors.lastname: Ribati
authors.forename: Jan
authors.initials: J
authors.lastname: Brabender
authors.forename: Carsten
authors.initials: C
authors.lastname: Zobel
authors.forename: Konrad F
authors.initials: KF
authors.lastname: Frank
authors.forename: Jens
authors.initials: J
authors.lastname: Wippermann
authors.forename: Robert H G
authors.initials: RH
authors.lastname: Schwinger
authors.forename: Klara
authors.initials: K
authors.lastname: Brixius
authors.forename: Jochen
authors.initials: J
authors.lastname: Müller-Ehmsen
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006325:Heart Atria / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D007537:Isometric Contraction; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium