Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes

Lacombe, Véronique A.; Viatchenko‐Karpinski, Serge; Terentyev, Dmitry; Sridhar, Arun; Emani, Sitaramesh; Bonagura, John D.; Feldman, David S.; Györke, Sándor; Carnes, Cynthia A.

doi:10.1152/ajpregu.00059.2007

Cited by 117 publications

(144 citation statements)

References 53 publications

Supporting

Mentioning

122

Contrasting

Unclassified

Order By: Relevance

“…Reduced left ventricular (LV) systolic pressure and diminished ±dP/dt (rate of pressure rise or fall during systole and diastole, respectively) have been demonstrated using LV catheterization (Kajstura et al, 2001;Van Linthout et al, 2008). Diastolic dysfunction has been suggested by increased LV diastolic pressure, measured by catheterization, and by abnormal patterns of mitral inflow and pulmonary venous flow using Doppler echocardiography (Kajstura et al, 2001;Lacombe et al, 2007). In vitro, peak LV pressure and ±dP/dt are reduced in Langendorffperfused hearts (Trost et al, 2002;Suarez et al, 2004;Suarez et al, 2008).…”

Section: Models Of Type 1 Diabetes the Streptozotocin (Stz) Modelmentioning

confidence: 99%

Rodent models of diabetic cardiomyopathy

Bugger

Abel

2009

Disease Models &Amp; Mechanisms

248

198

View full text Add to dashboard Cite

Diabetic cardiomyopathy increases the risk of heart failure in individuals with diabetes, independently of co-existing coronary artery disease and hypertension. The underlying mechanisms for this cardiac complication are incompletely understood. Research on rodent models of type 1 and type 2 diabetes, and the use of genetic engineering techniques in mice, have greatly advanced our understanding of the molecular mechanisms responsible for human diabetic cardiomyopathy. The adaptation of experimental techniques for the investigation of cardiac physiology in mice now allows comprehensive characterization of these models. The focus of the present review will be to discuss selected rodent models that have proven to be useful in studying the underlying mechanisms of human diabetic cardiomyopathy, and to provide an overview of the characteristics of these models for the growing number of investigators who seek to understand the pathology of diabetes-related heart disease.

show abstract

Section: Models Of Type 1 Diabetes the Streptozotocin (Stz) Modelmentioning

confidence: 99%

Rodent models of diabetic cardiomyopathy

Bugger

Abel

2009

Disease Models &Amp; Mechanisms

248

198

View full text Add to dashboard Cite

show abstract

“…These alterations are the result of changes in the expression and function of SR Ca 2+ handling proteins; SERCA2a, NCX and RyR expressions are reduced, whereas phospholamban expression is increased and its phosphorylation decreased. 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].…”

Section: Diabetic Cardiomyopathymentioning

confidence: 99%

“…As a consequence, SR Ca 2+ load is reduced, and SR Ca 2+ release and re-uptake are impaired [181,182]. 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].…”

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

172

149

View full text Add to dashboard Cite

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...

show abstract

“…In addition, accumulating evidence suggests that increased protein O-GlcNAcylation may also mediate the adverse effects of diabetes on the heart. Diabetes leads to abnormal cardiomyocyte excitation-contraction (E-C) coupling, including prolonged action potential duration, slowed cytosolic Ca 2ϩ removal, and prolonged myocyte relaxation (37,123). In isolated ventricular myocytes, these mechanical dysfunctions can be observed as early as a few days after STZ-induced diabetes (175) and after long-term diet-induced insulin resistance (56,213).…”

Section: O-glcnacylation and Cardiomyocyte Dysfunctionmentioning

confidence: 99%

ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Laczy¹,

Hill²,

Wang³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

143

135

View full text Add to dashboard Cite

The posttranslational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide ␤-N-acetylglucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification. Protein O-GlcNAcylation is rapidly emerging as a key regulator of critical biological processes including nuclear transport, translation and transcription, signal transduction, cytoskeletal reorganization, proteasomal degradation, and apoptosis. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are both major hallmarks of diabetes mellitus and diabetes-related cardiovascular complications. Conversely, there is a growing body of data demonstrating that the acute activation of O-GlcNAc levels is an endogenous stress response designed to enhance cell survival. Reports on the effect of altered O-GlcNAc levels on the heart and cardiovascular system have been growing rapidly over the past few years and have implicated a role for O-GlcNAc in contributing to the adverse effects of diabetes on cardiovascular function as well as mediating the response to ischemic injury. Here, we summarize our present understanding of protein O-GlcNAcylation and its effect on the regulation of cardiovascular function. We examine the pathways regulating protein O-GlcNAcylation and discuss, in more detail, our understanding of the role of O-GlcNAc in both mediating the adverse effects of diabetes as well as its role in mediating cellular protective mechanisms in the cardiovascular system. In addition, we also explore the parallels between O-GlcNAc signaling and redox signaling, as an alternative paradigm for understanding the role of O-GlcNAcylation in regulating cell function. hexosamine biosynthesis; protein O-glycosylation; ␤-N-acetylglucosamine transferase; diabetes mellitus POSTTRANSLATIONAL MODIFICATION (PTM) of proteins is a common mechanism for the modulation of protein function, location, and turnover. Although protein phosphorylation is probably the most widely studied form of PTM, there are many other PTMs, including acylation, ubiquitylation, methylation, acetylation, thiolation, nitration, and glycosylation (107). The focus of this review is protein glycosylation, specifically, O-glycosylation of nuclear and cytoplasmic proteins. Classical protein glycosylation occurs in the endoplasmic reticulum and Golgi, leading to the formation of stable and complex elongated oligosaccharide structures via both N-linkage on asparagine and O-linkage on the hydroxy amino acids serine and threonine in addition to hydroxyproline, hydroxylysine, and tyrosine residues of proteins that become secreted or membrane component glycoproteins (189). In contrast, glycosylation of nuclear and cytoplasmic proteins is a rapid and dynamic modification of serine or threonine residues by the O-linked attachment of the monosaccharide ␤-N-acetylglucosamine (OGlcNAc) (97,195); this process is referred to as protein O-GlcNAcylation to contrast it wi...

show abstract

Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes

Cited by 117 publications

References 53 publications

Rodent models of diabetic cardiomyopathy

Rodent models of diabetic cardiomyopathy

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

ProteinO-GlcNAcylation: a new signaling paradigm for the cardiovascular system

Contact Info

Product

Resources

About