Diminished Expression of Sarcoplasmic Reticulum Ca2+-ATPase and Ryanodine Sensitive Ca2+Channel mRNA in Streptozotocin-induced Diabetic Rat Heart

Teshima, Yasushi; Takahashi, Naohiko; Saikawa, Tetsunori; Hara, Masahide; Yasunaga, Seikoh; Hidaka, Shigekazu; Sakata, Toshiie

doi:10.1006/jmcc.2000.1107

Cited by 97 publications

(71 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Two weeks of insulin treatment, initiated after 6 weeks of STZ-induced diabetes, minimized and/or prevented loss in transcription of RyR2 mRNA (96.9 Ϯ 4.4% of control, P Ͼ 0.05). These data are consistent with previous studies showing that transcription of mRNA encoding RyR2 decreases with diabetes, and this decrease was prevented or minimized with insulin treatment (11,14,15). Quantitation of mRNA encoding RAGE from 8C, 8D, and 6D-2I rat hearts.…”

Section: Induction Of Experimental Stz-induced Diabetessupporting

confidence: 92%

Chronic Diabetes Increases Advanced Glycation End Products on Cardiac Ryanodine Receptors/Calcium-Release Channels

et al. 2003

View full text Add to dashboard Cite

Decrease in cardiac contractility is a hallmark of chronic diabetes. Previously we showed that this defect results, at least in part, from a dysfunction of the type 2 ryanodine receptor calcium-release channel (RyR2). The mechanism(s) underlying RyR2 dysfunction is not fully understood. The present study was designed to determine whether non-cross-linking advanced glycation end products (AGEs) on RyR2 increase with chronic diabetes and if formation of these post-translational complexes could be attenuated with insulin treatment. Overnight digestion of RyR2 from 8-week control animals (8C) with trypsin afforded 298 peptides with monoisotopic mass (M؉H ؉ ) >500. Digestion of RyR2 from 8-week streptozotocin-induced diabetic animals (8D) afforded 21% fewer peptides, whereas RyR2 from 6-week diabetic/2-week insulin-treated animals generated 304 peptides. Using an in-house PERLscript algorithm, search of matrix-assisted laser desorption ionization-time of flight mass data files identified several M؉H ؉ peaks corresponding to theoretical RyR2 peptides with single N ⑀ -(carboxymethyl)-lysine, imidazolone A, imidazone B, pyrraline, or 1-alkyl-2-formyl-3,4-glycosyl pyrrole modification that were present in 8D but not 8C. Insulin treatment minimized production of some of these nonenzymatic glycation products. These data show for the first time that AGEs are formed on intracellular RyR2 during diabetes. Because AGE complexes are known to compromise protein activity, these data suggest a potential mechanism for diabetesinduced RyR2 dysfunction. Diabetes 52:1825-1836, 2003 A significant percentage of patients with diabetes (both type 1 and type 2) develop a unique cardiomyopathy that is independent of coronary atherosclerosis (1-3). This "diabetic cardiomyopathy" as it is termed starts off with asymptomatic left ventricular diastolic dysfunction (slowing of relaxation kinetics). As the disease progresses, systolic function becomes compromised, leading to an increase in incidence of morbidity and mortality (4 -6).The release of calcium ions from internal sarcoplasmic reticulum via the type 2 ryanodine receptor calciumrelease channel (RyR2) is an integral step in the cascade of events leading to cardiac muscle contraction (7). We and others have shown that expression of this protein decreases in hearts of chronic diabetic patients (8,9) as well as in the streptozotocin (STZ)-induced diabetic rats (10 -13). Using the latter model, we found that in addition to a decrease in expression of RyR2, its functional integrity is also compromised in diabetes (14,15). This dysfunction is manifested as a decrease in RyR2 ability to bind the specific ligand [ 3 H]ryanodine and a slowing in its electrophoretic mobility using denaturing SDS-PAGE.Two distinct and separate types of post-translational modifications are likely to be induced by diabetes. First, it is well known that metabolic changes brought about by diabetes increase production of reactive oxygen species (e.g., -18]). These free radical and nonradical species react with several a...

show abstract

Section: Induction Of Experimental Stz-induced Diabetessupporting

confidence: 92%

Chronic Diabetes Increases Advanced Glycation End Products on Cardiac Ryanodine Receptors/Calcium-Release Channels

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The down-regulation of RyR2 mRNA gene expression induced by food restriction observed in the present study is also observed in other situations such as cardiac hypertrophy, diabetes mellitus and heart failure (15)(16)(17).…”

Section: Controlsupporting

confidence: 84%

Down-regulation of the cardiac sarcoplasmic reticulum ryanodine channel in severely food-restricted rats

Vizotto

Carvalho

Sugizaki

et al. 2007

Braz J Med Biol Res

View full text Add to dashboard Cite

We have shown that myocardial dysfunction induced by food restriction is related to calcium handling. Although cardiac function is depressed in food-restricted animals, there is limited information about the molecular mechanisms that lead to this abnormality. The present study evaluated the effects of food restriction on calcium cycling, focusing on sarcoplasmic Ca 2+ -ATPase (SERCA2), phospholamban (PLB), and ryanodine channel (RYR2) mRNA expressions in rat myocardium. Male Wistar-Kyoto rats, 60 days old, were submitted to ad libitum feeding (control rats) or 50% diet restriction for 90 days. The levels of left ventricle SERCA2, PLB, and RYR2 were measured using semi-quantitative RT-PCR. Body and ventricular weights were reduced in 50% food-restricted animals. RYR2 mRNA was significantly decreased in the left ventricle of the foodrestricted group (control = 5.92 ± 0.48 vs food-restricted group = 4.84 ± 0.33, P < 0.01). The levels of SERCA2 and PLB mRNA were similar between groups (control = 8.38 ± 0.44 vs food-restricted group = 7.96 ± 0.45, and control = 1.52 ± 0.06 vs food-restricted group = 1.53 ± 0.10, respectively). Down-regulation of RYR2 mRNA expressions suggests that chronic food restriction promotes abnormalities in sarcoplasmic reticulum Ca 2+ release. Key wordsFood restriction induces beneficial health effects such as increased longevity and retards or prevents a broad spectrum of agerelated pathophysiological changes such as loss of skeletal muscle mass, diabetes mellitus, hypertension, and cancer (1-3). Recent research from our laboratory has shown that 50% food restriction promotes left ventricular dysfunction and increases contraction and relaxation times in isolated papillary muscle of both young Wistar-Kyoto normotensive and spontaneously hypertensive rats (4-7). Sugizaki et al. (7) observed that myocardial dysfunction in food-restricted rats is related to calcium handling. However, these investigators were unable to identify calcium handling site abnormalities.Few studies have analyzed the molecular

show abstract

“…Although a reduction of SR Ca 2ϩ -uptake, Ca 2ϩ -release, and ryanodine binding has been previously demonstrated in the diabetic heart (5,6), the mechanisms underlying alterations in SR function were not fully established. In this regard, the decrease in protein contents of RyR, SERCA2a, and PLB observed in the diabetic heart in this and other studies (15,16) could explain the depression in SR Ca 2ϩ -uptake and -release activities. However, it should be pointed out that the depression of the Ca 2ϩ -cycling protein levels may represent one of several factors, such as increased phospholipid and fatty acid content in …”

Section: Discussionsupporting

confidence: 66%

Depressed Levels of Ca2+-Cycling Proteins May Underlie Sarcoplasmic Reticulum Dysfunction in the Diabetic Heart

et al. 2001

View full text Add to dashboard Cite

In view of the depressed sarcoplasmic reticulum (SR) Ca 2؉-pump and Ca 2؉ -release activities in the diabetic heart and the critical role of phosphorylation in regulating the SR function, we examined the status of Ca -pump ATPase, and phospholamban. On the other hand, the CaMK-and PKA-mediated phosphorylations of these Ca 2؉ -cycling proteins, the endogenous SR CaMK and PKA activities, and the endogenous SR and cytosolic phosphatase activities were increased in the diabetic heart. Treatment of 3-week diabetic animals with insulin partially or fully prevented the diabetesinduced changes in cardiac performance, SR Ca 2؉ -uptake and -release activites, and SR protein content, whereas the diabetes-induced changes in SR CaMK-and PKA-mediated phosphorylations and activities, as well as phosphatase activities, were not significantly affected. These results suggest that the reduced content of the Ca 2؉ -cycling proteins, unlike alterations in PKA and phosphatase activities, appear to be the major defect underlying SR dysfunction in the diabetic heart.

show abstract

Diminished Expression of Sarcoplasmic Reticulum Ca2+-ATPase and Ryanodine Sensitive Ca2+Channel mRNA in Streptozotocin-induced Diabetic Rat Heart

Cited by 97 publications

References 13 publications

Chronic Diabetes Increases Advanced Glycation End Products on Cardiac Ryanodine Receptors/Calcium-Release Channels

Chronic Diabetes Increases Advanced Glycation End Products on Cardiac Ryanodine Receptors/Calcium-Release Channels

Down-regulation of the cardiac sarcoplasmic reticulum ryanodine channel in severely food-restricted rats

Depressed Levels of Ca2+-Cycling Proteins May Underlie Sarcoplasmic Reticulum Dysfunction in the Diabetic Heart

Contact Info

Product

Resources

About