Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients.
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.
Reuter
Hannes
H
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
Grönke
Sabine
S
Adam
Christian
C
Ribati
Maida
M
Brabender
Jan
J
Zobel
Carsten
C
Frank
Konrad F
KF
Wippermann
Jens
J
Schwinger
Robert H G
RH
Brixius
Klara
K
Müller-Ehmsen
Jochen
J
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
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