Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca2+-ATPase.
Prolongation of relaxation is a hallmark of diabetic cardiomyopathy. Most studies attribute this defect to decreases in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) expression and SERCA2a-to-phospholamban (PLB) ratio. Since its turnover rate is slow, SERCA2a is susceptible to posttranslational modifications during diabetes. These modifications could in turn compromise conformational rearrangements needed to translocate calcium ions, also leading to a decrease in SERCA2a activity. In the present study one such modification was investigated, namely advanced glycation end products (AGEs). Hearts from 8-week streptozotocin-induced diabetic (8D) rats showed typical slowing in relaxation, confirming cardiomyopathy. Hearts from 8D animals also expressed lower levels of SERCA2a protein and higher levels of PLB. Analysis of matrix-assisted laser desorption/ionization time-of-flight mass data files from trypsin-digested SERCA2a revealed several cytosolic SERCA2a peptides from 8D modified by single noncrosslinking AGEs. Crosslinked AGEs were also found. Lysine residues within actuator and phosphorylation domains were cross-linked to arginine residues within the nucleotide binding domain via pentosidine AGEs. Two weeks of insulin-treatment initiated after 6 weeks of diabetes attenuated these changes. These data demonstrate for the first time that AGEs are formed on SERCA2a during diabetes, suggesting a novel mechanism by which cardiac relaxation can be slowed during diabetes.
Bidasee
Keshore R
KR
Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska, USA. kbidasee@unmc.edu
Zhang
Yinong
Y
Shao
Chun Hong
CH
Wang
Mu
M
Patel
Kaushik P
KP
Dincer
U Deniz
UD
Besch
Henry R
HR
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D007328:Insulin / Q000627:therapeutic use; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
D017127:Glycation End Products, Advanced; D007328:Insulin; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol