Diabetes decreases mRNA levels of calcium-release channels in human atrial appendage

Güner, Şahika; Arıoglu, Ebru; Tay, Aydin; Tasdelen, Atalay; Aşlamacı, Sait; Bidasee, Keshore R.; Dinçer, Ü. Deniz

doi:10.1023/b:mcbi.0000041856.92497.0c

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…One of these proteins is RyR2, the channel through which calcium ions leave the sarcoplasmic reticulum to trigger cardiac contraction. We and others have shown that expression of this protein decreases in hearts of chronic diabetic patients (8,9). Using the STZ-induced diabetic rat model, we have also shown that in addition to a decrease in expression, the functional integrity of RyR2 decreases with diabetes (14,15,19).…”

Section: Discussionsupporting

confidence: 52%

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

et al. 2003

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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...

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Section: Discussionsupporting

confidence: 52%

“…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).…”

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confidence: 99%

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

et al. 2003

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“…As a consequence, SR Ca 2+ load is reduced, and SR Ca 2+ release and re-uptake are impaired [181,182]. Interestingly, an increased [184,185]. Both increased and decreased IP 3 production in response to α-adrenergic stimulation has been reported in diabetes [186,187].…”

Section: Diabetic Cardiomyopathymentioning

confidence: 99%

“…Interestingly, an increased propensity toward arrhythmogenic afterdepolarizations has been observed in diabetic cardiomyocytes [182]. Insulin increases IP 3 concentration and triggers arrhythmic Ca 2+ release events in myocytes from diabetic ob/ob mice -but not from wild-type mice -and this effect is mediated via IP 3 signaling [183].IP 3 R expression (type 1 and type 2 IP 3 Rs) is unaltered in ventricles from ob/ob mice [183], but decreased in a diabetes model in the rat and in atrium from diabetic patients [184,185]. Both increased and decreased IP 3 production in response to α-adrenergic stimulation has been reported in diabetes [186,187].…”

Section: Diabetic Cardiomyopathymentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

169

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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“…RNA samples were used as templates for synthesis of firststrand cDNAs as previously described (10). Briefly, 1 l of oligo dT15 primer (Promega) was added to equivalent amounts of total RNA obtained from coronary arteries isolated from control (n ϭ 4) and high-fat diet dogs (n ϭ 4).…”

Section: Thismentioning

confidence: 99%

Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction

Knudson

Dinçer

Dick³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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tinemia, associated with prediabetes, is an independent risk factor for coronary artery disease and a mediator of coronary endothelial dysfunction. We previously demonstrated that acutely raising the leptin concentration to levels comparable with those observed in human obesity significantly attenuates coronary dilation/relaxation to acetylcholine (ACh) both in vivo in anesthetized dogs and in vitro in isolated canine coronary rings. Accordingly, the purpose of this investigation was to extend these studies to a model of prediabetes with chronic hyperleptinemia. In the present investigation, experiments were conducted on control and high-fat-fed dogs. High-fat feeding caused a significant increase (131%) in plasma leptin concentration. Furthermore, in high-fat-fed dogs, exogenous leptin did not significantly alter vascular responses to ACh in vivo or in vitro. Coronary vasodilator responses to ACh (0.3-30.0 g/min) and sodium nitroprusside (1.0 -100.0 g/min) were not significantly different from those observed in control dogs. Also, high-fat feeding did not induce a switch to an endothelium-derived hyperpolarizing factor as a major mediator of muscarinic coronary vasodilation, because dilation to ACh was abolished by combined pretreatment with N -nitro-Larginine methyl ester (150 g/min ic) and indomethacin (10 mg/kg iv). Quantitative, real-time PCR revealed no significant difference in coronary artery leptin receptor gene expression between control and high-fat-fed dogs. In conclusion, high-fat feeding induces resistance to the coronary vascular effects of leptin, and this represents an early protective adaptation against endothelial dysfunction. The resistance is not due to altered endothelium-dependent or -independent coronary dilation, increased endothelium-derived hyperpolarizing factor, or changes in coronary leptin receptor mRNA levels. coronary circulation; metabolic syndrome; obesity HYPERLEPTINEMIA, universal in the human obese population (7), has recently been deemed an independent risk factor for cardiovascular disease (35) and, more specifically, a predictor of first myocardial infarction (43) and an independent risk factor for ischemic and hemorrhagic stroke (44). Since its discovery (53), leptin has been shown to promote platelet aggregation and thrombosis (3,16,17). Additionally, leptin is linked to the production of acute phase reactants (TNF-␣, IL-6, and IL-12) (22), neointimal growth in mice (38), superoxide production in aortic endothelium (50), and calcification of vascular smooth muscle cells (30). The leptin receptor is a type I cytokine receptor, similar to gp130 and granulocyte colony-stimulating factor receptors (45, 51), and elevated plasma leptin levels occur concurrently with elevated IL-6 and C-reactive protein in human obesity-related conditions (19,23,27). Despite the superfluity of studies linking leptin to various atherogenic processes, few studies to date have examined the direct effects of leptin on the coronary circulation.We (15) recently demonstrated that acutely raising coro...

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Diabetes decreases mRNA levels of calcium-release channels in human atrial appendage

Cited by 21 publications

References 40 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

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction

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