Hexosamine Pathway Is Responsible for Inhibition by Diabetes of Phenylephrine-Induced Inotropy

Pang, Yi; Bounelis, Pam; Chatham, John C.; Marchase, Richard B.

doi:10.2337/diabetes.53.4.1074

Cited by 52 publications

(60 citation statements)

References 53 publications

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“…In contrast, inhibition of NCX, which is also reportedly activated by PE (116), had no effect on PEinduced inotropic response (82). Notably, SKF96365 had no effect on the positive inotropic response to the ␤-adrenergic agonist isoproterenol, demonstrating that SOCE appears to be specific in mediating the effects of ␣-adrenergic and not ␤-adrenergic agonists (82). This specificity is likely due to the fact that unlike ␣-adrenergic agonists, ␤-adrenergic agonists do not generate IP 3 and do not lead to Ca 2ϩ store depletion.…”

Section: Orai1/trpcmentioning

confidence: 54%

“…In addition to stimulating cardiomyocyte hypertrophy, PE, an ␣-adrenergic agonist, is a potent positive inotropic agent in the heart. Interestingly, we reported that treatment of the isolated perfused heart with the SOCE inhibitor SKF96365 significantly blunted the response to PE compared with untreated control hearts (82). In contrast, inhibition of NCX, which is also reportedly activated by PE (116), had no effect on PEinduced inotropic response (82).…”

Section: Orai1/trpcmentioning

confidence: 96%

“…Interestingly, we reported that treatment of the isolated perfused heart with the SOCE inhibitor SKF96365 significantly blunted the response to PE compared with untreated control hearts (82). In contrast, inhibition of NCX, which is also reportedly activated by PE (116), had no effect on PEinduced inotropic response (82). Notably, SKF96365 had no effect on the positive inotropic response to the ␤-adrenergic agonist isoproterenol, demonstrating that SOCE appears to be specific in mediating the effects of ␣-adrenergic and not ␤-adrenergic agonists (82).…”

Section: Orai1/trpcmentioning

confidence: 99%

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STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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111

102

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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Section: Orai1/trpcmentioning

confidence: 54%

Section: Orai1/trpcmentioning

confidence: 96%

Section: Orai1/trpcmentioning

confidence: 99%

See 1 more Smart Citation

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

111

102

View full text Add to dashboard Cite

show abstract

“…In the intact heart, increased HBP flux induced by either short-term STZ-induced diabetes or after acute glucosamine treatment blunted the positive inotropic responses to the ␣-adrenergic agonist PE, whereas the response to ␤-adrenergic stimulation was unaffected (168). In ventricular myocytes, increased O-GlcNAcylation attenuated the increase in cytosolic Ca 2ϩ levels induced by PE and other IP 3 -generating agonists such as angiotensin II (157,169).…”

Section: O-glcnacylation and Cardiomyocyte Dysfunctionmentioning

confidence: 88%

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

Laczy¹,

Hill²,

Wang³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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143

135

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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...

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“…First described in nonexcitable cells, CCE has now been shown to coexist with L-type channels in smooth and skeletal muscle cells (17,35) and in both neonatal and adult cardiomyocytes (12,13,31). The TRPC protein family has been a prime candidate for CCE channel proteins (14) and TRPC1, -3, -4, -5, and -6 have all been identified in rat and mouse hearts (14,28,30).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes

Shan

Marchase²,

Chatham

2008

American Journal of Physiology-Cell Physiology

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Shan D, Marchase RB, Chatham JC. Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes. Am J Physiol Cell Physiol 294: C833-C841, 2008. First published January 9, 2008 doi:10.1152/ajpcell.00313.2007.-An increase in cytosolic Ca 2ϩ via a capacitative calcium entry (CCE)-mediated pathway, attributed to members of the transient receptor potential (TRP) superfamily, TRPC1 and TRPC3, has been reported to play an important role in regulating cardiomyocyte hypertrophy. Increased cytosolic Ca 2ϩ also plays a critical role in mediating cell death in response to ischemiareperfusion (I/R). Therefore, we tested the hypothesis that overexpression of TRPC3 in cardiomyocytes will increase sensitivity to I/R injury. Adult cardiomyocytes isolated from wild-type (WT) mice and from mice overexpressing TRPC3 in the heart were subjected to 90 min of ischemia and 3 h of reperfusion. After I/R, viability was 51 Ϯ 1% in WT mice and 42 Ϯ 5% in transgenic mice (P Ͻ 0.05). Apoptosis assessed by annexin V was significantly increased in the TRPC3 group compared with WT (32 Ϯ 1% vs. 21 Ϯ 3%; P Ͻ 0.05); however, there was no significant difference in necrosis between groups. Treatment of TRPC3 cells with the CCE inhibitor SKF-96365 (0.5 M) significantly improved cellular viability (54 Ϯ 4%) and decreased apoptosis (15 Ϯ 4%); in contrast, the L-type Ca 2ϩ channel inhibitor verapamil (10 M) had no effect. Calpain-mediated cleavage of ␣-fodrin was increased approximately threefold in the transgenic group following I/R compared with WT (P Ͻ 0.05); this was significantly attenuated by SKF-96365. The calpain inhibitor PD-150606 (25 M) attenuated the increase in both ␣-fodrin cleavage and apoptosis in the TPRC3 group. Increased TRPC3 expression also increased sensitivity to Ca 2ϩ overload stress, but it did not affect the response to TNF-␣-induced apoptosis. These results suggest that CCE mediated via TRPC may play a role in cardiomyocyte apoptosis following I/R due, at least in part, to increased calpain activation.

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Hexosamine Pathway Is Responsible for Inhibition by Diabetes of Phenylephrine-Induced Inotropy

Cited by 52 publications

References 53 publications

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

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

Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes

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