Key result
Although MGO, GO, and 4-HNE alter RyR2 and SERCA2 function in vitro, only glucose-derived MGO and GO preferentially form adducts on these proteins in a rat model of type 1 diabetes.
Glucose-derived methylglyoxal and glyoxal preferentially form adducts on cardiac RyR2 and SERCA2 in diabetic cardiomyopathy, potentially contributing to calcium handling disturbances.
Posttranslational modification of cardiac type 2 ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA2) by reactive carbonyl species (RCS) is emerging as a leading cause for disturbances in the orchestrated release of Ca 2+ from and reuptake into the sarcoplasmic reticulum (SR) in diabetes. What is less clear at this time is which of the many RCS that are upregulated in diabetes chemically modify and impair the functions of RyR2 and SERCA2. This study uses in vitro assays to delineate the impact of key RCS that are upregulated during diabetes glyoxal (GO), methylglyoxal (MGO) and 4‐hydrononenal (4‐HNE) on functions of RyR2 and SERCA2. It also used adduct‐specific antibodies to determine if GO, MGO, 4HNE and malondialdehyde (MDA) formed adducts on RyR2 and SERCA2 in a rat model of type 1 diabetes. In [ 3 H]ryanodine binding and lipid bilayer assays, MGO, GO and 4HNE binded to and modulated the open probability (P o ) and/or conductance of RyR2 with varying potencies, establishing that they are capable of interacting with RyR2. In Ca 2+ uptake assays, MGO, GO and 4‐HNE also dose‐dependently modulated the ability of SERCA2 to transport Ca 2+ . Interestingly, RyR2 and SERCA2 isolated from hearts of rats with diabetic cardiomyopathy contained MGO and GO but not 4‐HNE MDA adducts. From these data that although MGO, GO and 4‐HNE are capable of altering the function of RyR2 and SERCA2 in vitro assays, only glucose‐derived MGO and GO preferentially react with RyR2 and SERCA2 to form adducts. Reasons for this selectivity will be discussed. Supported in part by NIH HL085061
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Bidasee et al. (2013) studied Type 1 diabetes and diabetic cardiomyopathy. Reactive carbonyl species (glyoxal, methylglyoxal, 4-hydroxynonenal, malondialdehyde) was evaluated on Adduct formation on RyR2 and SERCA2 and modulation of their function. Although MGO, GO, and 4-HNE alter RyR2 and SERCA2 function in vitro, only glucose-derived MGO and GO preferentially form adducts on these proteins in a rat model of type 1 diabetes.
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