John Chatham | University of Alabama at Birmingham (original) (raw)

Papers by John Chatham

Research paper thumbnail of Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation

American Journal of Physiology Heart and Circulatory Physiology, May 1, 2007

We have shown that in the perfused heart glucosamine improved functional recovery following ische... more We have shown that in the perfused heart glucosamine improved functional recovery following ischemia and this appeared to be mediated via an increase in O-Linked N-acetylglucosamine (O-GlcNAc) levels on nucleocytoplasmic proteins. Several kinase pathways, specifically Akt and the mitogen activated protein kinases (MAPK) p38 and ERK1/2, which have been implicated in ischemic cardioprotection, have been reported to be modified in response to increased O-GlcNAc levels. Therefore, the goals of this study were to determine the effect of ischemia on O-GlcNAc levels and to evaluate whether the cardioprotection resulting from glucosamine treatment could be attributed to changes in ERK1/2, Akt and p38 phosphorylation. Isolated rat hearts were perfused with or without 5mM glucosamine and were subjected to 5, 10 or 30 min low flow ischemia (LFI) or 30 min LFI and 60min reperfusion. Glucosamine treatment attenuated ischemic contracture and improved functional recovery at the end of reperfusion. Glucosamine treatment increased flux through the hexosamine biosynthesis pathway and increased O-GlcNAc levels but had no effect on ATP levels. Glucosamine did not alter the response of either ERK1/2 or Akt to ischemia/reperfusion; however it significantly attenuated the ischemia-induced increase in p38 phosphorylation and paradoxically increased p38 phosphorylation at the end of reperfusion. These data support the notion that O-GlcNAc may play an important role as an internal stress response and that glucosamine-induced cardioprotection may be mediated via the p38 MAPK pathway.

Research paper thumbnail of Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal

The Biochemical Journal, Oct 1, 2009

Mitochondria play a critical role in mediating the cellular response to oxidants formed during ac... more Mitochondria play a critical role in mediating the cellular response to oxidants formed during acute and chronic cardiac dysfunction. It is widely assumed that, as cells are subject to stress, mitochondria are capable of drawing upon a "reserve capacity" which is available to serve the increased energy demands for maintenance of organ function, cellular repair, or detoxification of reactive species. This hypothesis further implies that impairment or depletion of this putative reserve capacity ultimately leads to excessive protein damage and cell death. However, it has been difficult to fully evaluate this hypothesis since much of our information about the response of the mitochondrion to oxidative stress derives from studies on mitochondria isolated from their cellular context. Therefore, the goal of this study was to determine whether "bioenergetic reserve capacity" does indeed exist in the intact myocyte and whether it is utilized in response to stress induced by the pathologically relevant reactive lipid species 4-hydroxynonenal (HNE). We found that intact rat neonatal ventricular myocytes exhibit a substantial bioenergetic reserve capacity under basal conditions; however, on exposure to pathologically relevant concentrations of HNE, oxygen consumption was increased until this reserve capacity was depleted. Exhaustion of the reserve capacity by HNE treatment resulted in inhibition of respiration concomitant with protein modification and cell death. These data suggest that oxidized lipids could contribute to myocyte injury by decreasing the bioenergetic reserve capacity. Furthermore, these studies demonstrate the utility of measuring the bioenergetic reserve capacity for assessing or predicting the response of cells to stress.

Research paper thumbnail of Effect of ischemia-reperfusion on O-GlcNAcylation of specific proteins in isolated rat hearts

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart

American Journal of Physiology Endocrinology and Metabolism, May 1, 2004

Research paper thumbnail of Hexosamine Biosynthesis and Protein O-Glycosylation: The First Line of Defense Against Stress, Ischemia, and Trauma

Shock, 2007

An early and rapid response to severe injury or trauma is the development of hyperglycemia, which... more An early and rapid response to severe injury or trauma is the development of hyperglycemia, which has long been thought to be an essential survival response by providing fuel for vital organ systems and facilitating mobilization of interstitial fluid reserves by increasing osmolarity. However, glucose can also be metabolized via the hexosamine biosynthesis pathway (HBP), leading to the synthesis of uridine diphosphate N-acetyl-glucosamine(UDP-GlcNAc). UDP-GlcNAc is a substrate for the addition, via an O-linkage, of a single N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins (O-glycosylation, O-GlcNAc). There is increasing appreciation that protein O-glycosylation is a highly dynamic posttranslational modification that plays a key role in signal transduction pathways. Sustained increases in O-GlocNAc have been implicated in the development of diabetes and diabetic complications; however, recent studies have demonstrated that stress leads to a transient increase in O-GlcNAc levels that is associated with increased tolerance to stress. Indeed, activation of pathways leading to O-GlcNAc formation improves cell survival after I/R injury, whereas inhibition of O-GlcNAc formation decreases cell survival. In addition, in rodent models of trauma-hemorrhage, increasing O-GlcNAc levels during resuscitation improves cardiac function and organ perfusion and attenuates the inflammatory response. At the cellular level, increasing O-GlcNAc levels attenuates nuclear factor-kappaB activation. It is noteworthy that other metabolic-based treatments for severe injury such as glucose-insulin-potassium and glutamine also lead to increased HBP flux and O-GlcNAc levels. The goal of this review is to summarize our current understanding of the role of the HBP and O-GlcNAc on the regulation of cell function and survival and to present evidence to support the notion that activation of these pathways represents a novel treatment strategy for severe injury and trauma.

Research paper thumbnail of Peroxisome proliferator-activated receptor {delta} is an essential transcriptional regulator for mitochondrial protection and biogenesis in adult heart

Circulation Research, Mar 19, 2010

RATIONALE: Peroxisome proliferator-activated receptors (PPARs) (alpha, gamma, and delta/beta) are... more RATIONALE: Peroxisome proliferator-activated receptors (PPARs) (alpha, gamma, and delta/beta) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARdelta deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy.OBJECTIVE: To explore the essential role of PPARdelta in the adult heart.METHODS AND RESULTS: We investigated the consequences of inducible short-term PPARdelta knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPARdelta knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPARgamma coactivator-1 were substantially decreased in the short-term PPARdelta deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARdelta knockout hearts. Consequently, PPARdelta deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy.CONCLUSIONS: PPARdelta is an essential regulator of cardiac mitochondrial protection and biogenesis and PPARdelta activation can be a potential therapeutic target for cardiac disorders.

Research paper thumbnail of 0347: Beneficial cardiovascular effects of O-GlcNAc stimulation in early phase of septic shock

Archives of Cardiovascular Diseases Supplements, 2016

Research paper thumbnail of Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein-associated O-GlcNAc

American Journal of Physiology Cell Physiology, 2007

We have previously reported that glucosamine protected neonatal rat ventricular myocytes (NRVMs) ... more We have previously reported that glucosamine protected neonatal rat ventricular myocytes (NRVMs) against ischemia/reperfusion (I/R) injury, and this was associated to an increase in protein O linked-N-acetylglucosamine (O-GlcNAc) levels. However, the protective effect of glucosamine could be mediated via pathways other that O-GlcNAc formation; thus, the initial goal of this study was to determine whether increasing O-GlcNAc transferase (OGT) expression, which catalyzes the formation of O-GlcNAc, had similar protective effect as glucosamine. To better understand the potential mechanism underlying O-GlcNAc-mediated cytoprotection we examined whether increased O-GlcNAc levels altered the expression and translocation of members of the Bcl-2 protein family. Both glucosamine (5mM) and OGT overexpression increased basal and I/R induced O-GlcNAc levels, significantly decreased cellular injury, and attenuated loss of cytochrome C. Both interventions also attenuated the loss of mitochondrial membrane potential induced by H 2 O 2 and were also associated with an increase in mitochondrial Bcl-2 levels, but had no effect on Bad on Bax levels. Compared to glucosamine and OGT overexpression, NButGT (100 µM), an inhibitor of O-GlcNAcase, was less protective against I/R and H 2 O 2 and did not affect Bcl-2 expression, despite a 5 to 10 fold greater increase in overall O-GlcNAc levels. Decreased OGT expression resulted in lower basal O-GlcNAc levels, prevented the I/R induced increase in O-GlcNAc and mitochondrial Bcl-2 and increased cellular injury. These results demonstrate that the protective effects of glucosamine are mediated via increased formation of O-GlcNAc and suggest that this is due in part to enhanced mitochondrial Bcl-2 translocation.

Research paper thumbnail of Glucosamine Inhibits TNF-{alpha}-Induced Expression of Inflammatory Mediators In Rat Aortic Smooth Muscle Cells through Inhibition of NF{kappa}B Activation

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of Abstract 36: Acute Inhibition Of O-GlcNAc Signaling Rescues Inotropic Responsiveness In Type 1 Diabetic Rat Hearts

Circulation Research, Jul 18, 2014

Research paper thumbnail of In the isolated perfused heart phenylephrine-induced activation of ERK is attenuated by glucosamine

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of The role of STIM1 and store operated calcium entry in glucose-induced insulin secretion

The Faseb Journal, Apr 1, 2013

Research paper thumbnail of Increasing levels of O-linked N-acetylglucosamine (O-GlcNAc) on cardiac proteins during reperfusion improves recovery following ischemia/reperfusion and attenuates calpain-mediated proteolysis

The Faseb Journal, Apr 1, 2007

Research paper thumbnail of Abnormal autophagic response contributes to cardiac dysfunction in diabetic rat hearts following pressure overload

The Faseb Journal, Apr 1, 2009

Research paper thumbnail of Acute effects of increased hexosamine biosynthesis and protein O-GlcNAcylation on cardiac gene expression

The Faseb Journal, Apr 1, 2010

Research paper thumbnail of Impaired cardiomyocyte autophagy in diabetes is associated with increased hexosamine biosynthesis and protein O-GlcNAc levels

The Faseb Journal, Apr 1, 2009

Research paper thumbnail of O-Glycosylation is Increased in the Tubuli and Glomeruli of Patients with Diabetic Nephropathy

The Faseb Journal, Apr 1, 2008

Research paper thumbnail of Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation

American Journal of Physiology Endocrinology and Metabolism, Aug 1, 1999

The aim of this study was to investigate the effect of increasing exogenous palmitate concentrati... more The aim of this study was to investigate the effect of increasing exogenous palmitate concentration on carbohydrate and palmitate oxidation in hearts from control and 1-wk diabetic rats. Hearts were perfused with glucose, [3-(13)C]lactate, and [U-(13)C]palmitate. Substrate oxidation rates were determined by combining (13)C-NMR glutamate isotopomer analysis of tissue extracts with measurements of oxygen consumption. Carbohydrate oxidation was markedly depressed after diabetes in the presence of low (0.1 mM) but not high (1.0 mM) palmitate concentration. Increasing exogenous palmitate concentration 10-fold resulted in a 7-fold increase in the contribution of palmitate to energy production in controls but only a 30% increase in the diabetic group. Consequently, at 0.1 mM palmitate, the rate of fatty acid oxidation was higher in the diabetic group than in controls; however, at 1.0 mM fatty acid oxidation, it was significantly depressed. Therefore, after 1 wk of diabetes, the major differences in carbohydrate and fatty acid metabolism occur primarily at low rather than high exogenous palmitate concentration.

Research paper thumbnail of Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

American Journal of Physiology Heart and Circulatory Physiology, Jul 1, 2004

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myo... more Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used (1)H and (13)C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and (13)C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a approximately 50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and approximately 30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia.

Research paper thumbnail of Peroxisome Proliferator-Activated Receptor Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart

Research paper thumbnail of Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation

American Journal of Physiology Heart and Circulatory Physiology, May 1, 2007

We have shown that in the perfused heart glucosamine improved functional recovery following ische... more We have shown that in the perfused heart glucosamine improved functional recovery following ischemia and this appeared to be mediated via an increase in O-Linked N-acetylglucosamine (O-GlcNAc) levels on nucleocytoplasmic proteins. Several kinase pathways, specifically Akt and the mitogen activated protein kinases (MAPK) p38 and ERK1/2, which have been implicated in ischemic cardioprotection, have been reported to be modified in response to increased O-GlcNAc levels. Therefore, the goals of this study were to determine the effect of ischemia on O-GlcNAc levels and to evaluate whether the cardioprotection resulting from glucosamine treatment could be attributed to changes in ERK1/2, Akt and p38 phosphorylation. Isolated rat hearts were perfused with or without 5mM glucosamine and were subjected to 5, 10 or 30 min low flow ischemia (LFI) or 30 min LFI and 60min reperfusion. Glucosamine treatment attenuated ischemic contracture and improved functional recovery at the end of reperfusion. Glucosamine treatment increased flux through the hexosamine biosynthesis pathway and increased O-GlcNAc levels but had no effect on ATP levels. Glucosamine did not alter the response of either ERK1/2 or Akt to ischemia/reperfusion; however it significantly attenuated the ischemia-induced increase in p38 phosphorylation and paradoxically increased p38 phosphorylation at the end of reperfusion. These data support the notion that O-GlcNAc may play an important role as an internal stress response and that glucosamine-induced cardioprotection may be mediated via the p38 MAPK pathway.

Research paper thumbnail of Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal

The Biochemical Journal, Oct 1, 2009

Mitochondria play a critical role in mediating the cellular response to oxidants formed during ac... more Mitochondria play a critical role in mediating the cellular response to oxidants formed during acute and chronic cardiac dysfunction. It is widely assumed that, as cells are subject to stress, mitochondria are capable of drawing upon a "reserve capacity" which is available to serve the increased energy demands for maintenance of organ function, cellular repair, or detoxification of reactive species. This hypothesis further implies that impairment or depletion of this putative reserve capacity ultimately leads to excessive protein damage and cell death. However, it has been difficult to fully evaluate this hypothesis since much of our information about the response of the mitochondrion to oxidative stress derives from studies on mitochondria isolated from their cellular context. Therefore, the goal of this study was to determine whether "bioenergetic reserve capacity" does indeed exist in the intact myocyte and whether it is utilized in response to stress induced by the pathologically relevant reactive lipid species 4-hydroxynonenal (HNE). We found that intact rat neonatal ventricular myocytes exhibit a substantial bioenergetic reserve capacity under basal conditions; however, on exposure to pathologically relevant concentrations of HNE, oxygen consumption was increased until this reserve capacity was depleted. Exhaustion of the reserve capacity by HNE treatment resulted in inhibition of respiration concomitant with protein modification and cell death. These data suggest that oxidized lipids could contribute to myocyte injury by decreasing the bioenergetic reserve capacity. Furthermore, these studies demonstrate the utility of measuring the bioenergetic reserve capacity for assessing or predicting the response of cells to stress.

Research paper thumbnail of Effect of ischemia-reperfusion on O-GlcNAcylation of specific proteins in isolated rat hearts

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart

American Journal of Physiology Endocrinology and Metabolism, May 1, 2004

Research paper thumbnail of Hexosamine Biosynthesis and Protein O-Glycosylation: The First Line of Defense Against Stress, Ischemia, and Trauma

Shock, 2007

An early and rapid response to severe injury or trauma is the development of hyperglycemia, which... more An early and rapid response to severe injury or trauma is the development of hyperglycemia, which has long been thought to be an essential survival response by providing fuel for vital organ systems and facilitating mobilization of interstitial fluid reserves by increasing osmolarity. However, glucose can also be metabolized via the hexosamine biosynthesis pathway (HBP), leading to the synthesis of uridine diphosphate N-acetyl-glucosamine(UDP-GlcNAc). UDP-GlcNAc is a substrate for the addition, via an O-linkage, of a single N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins (O-glycosylation, O-GlcNAc). There is increasing appreciation that protein O-glycosylation is a highly dynamic posttranslational modification that plays a key role in signal transduction pathways. Sustained increases in O-GlocNAc have been implicated in the development of diabetes and diabetic complications; however, recent studies have demonstrated that stress leads to a transient increase in O-GlcNAc levels that is associated with increased tolerance to stress. Indeed, activation of pathways leading to O-GlcNAc formation improves cell survival after I/R injury, whereas inhibition of O-GlcNAc formation decreases cell survival. In addition, in rodent models of trauma-hemorrhage, increasing O-GlcNAc levels during resuscitation improves cardiac function and organ perfusion and attenuates the inflammatory response. At the cellular level, increasing O-GlcNAc levels attenuates nuclear factor-kappaB activation. It is noteworthy that other metabolic-based treatments for severe injury such as glucose-insulin-potassium and glutamine also lead to increased HBP flux and O-GlcNAc levels. The goal of this review is to summarize our current understanding of the role of the HBP and O-GlcNAc on the regulation of cell function and survival and to present evidence to support the notion that activation of these pathways represents a novel treatment strategy for severe injury and trauma.

Research paper thumbnail of Peroxisome proliferator-activated receptor {delta} is an essential transcriptional regulator for mitochondrial protection and biogenesis in adult heart

Circulation Research, Mar 19, 2010

RATIONALE: Peroxisome proliferator-activated receptors (PPARs) (alpha, gamma, and delta/beta) are... more RATIONALE: Peroxisome proliferator-activated receptors (PPARs) (alpha, gamma, and delta/beta) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARdelta deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy.OBJECTIVE: To explore the essential role of PPARdelta in the adult heart.METHODS AND RESULTS: We investigated the consequences of inducible short-term PPARdelta knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPARdelta knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPARgamma coactivator-1 were substantially decreased in the short-term PPARdelta deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARdelta knockout hearts. Consequently, PPARdelta deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy.CONCLUSIONS: PPARdelta is an essential regulator of cardiac mitochondrial protection and biogenesis and PPARdelta activation can be a potential therapeutic target for cardiac disorders.

Research paper thumbnail of 0347: Beneficial cardiovascular effects of O-GlcNAc stimulation in early phase of septic shock

Archives of Cardiovascular Diseases Supplements, 2016

Research paper thumbnail of Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein-associated O-GlcNAc

American Journal of Physiology Cell Physiology, 2007

We have previously reported that glucosamine protected neonatal rat ventricular myocytes (NRVMs) ... more We have previously reported that glucosamine protected neonatal rat ventricular myocytes (NRVMs) against ischemia/reperfusion (I/R) injury, and this was associated to an increase in protein O linked-N-acetylglucosamine (O-GlcNAc) levels. However, the protective effect of glucosamine could be mediated via pathways other that O-GlcNAc formation; thus, the initial goal of this study was to determine whether increasing O-GlcNAc transferase (OGT) expression, which catalyzes the formation of O-GlcNAc, had similar protective effect as glucosamine. To better understand the potential mechanism underlying O-GlcNAc-mediated cytoprotection we examined whether increased O-GlcNAc levels altered the expression and translocation of members of the Bcl-2 protein family. Both glucosamine (5mM) and OGT overexpression increased basal and I/R induced O-GlcNAc levels, significantly decreased cellular injury, and attenuated loss of cytochrome C. Both interventions also attenuated the loss of mitochondrial membrane potential induced by H 2 O 2 and were also associated with an increase in mitochondrial Bcl-2 levels, but had no effect on Bad on Bax levels. Compared to glucosamine and OGT overexpression, NButGT (100 µM), an inhibitor of O-GlcNAcase, was less protective against I/R and H 2 O 2 and did not affect Bcl-2 expression, despite a 5 to 10 fold greater increase in overall O-GlcNAc levels. Decreased OGT expression resulted in lower basal O-GlcNAc levels, prevented the I/R induced increase in O-GlcNAc and mitochondrial Bcl-2 and increased cellular injury. These results demonstrate that the protective effects of glucosamine are mediated via increased formation of O-GlcNAc and suggest that this is due in part to enhanced mitochondrial Bcl-2 translocation.

Research paper thumbnail of Glucosamine Inhibits TNF-{alpha}-Induced Expression of Inflammatory Mediators In Rat Aortic Smooth Muscle Cells through Inhibition of NF{kappa}B Activation

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of Abstract 36: Acute Inhibition Of O-GlcNAc Signaling Rescues Inotropic Responsiveness In Type 1 Diabetic Rat Hearts

Circulation Research, Jul 18, 2014

Research paper thumbnail of In the isolated perfused heart phenylephrine-induced activation of ERK is attenuated by glucosamine

The Faseb Journal, Mar 1, 2008

Research paper thumbnail of The role of STIM1 and store operated calcium entry in glucose-induced insulin secretion

The Faseb Journal, Apr 1, 2013

Research paper thumbnail of Increasing levels of O-linked N-acetylglucosamine (O-GlcNAc) on cardiac proteins during reperfusion improves recovery following ischemia/reperfusion and attenuates calpain-mediated proteolysis

The Faseb Journal, Apr 1, 2007

Research paper thumbnail of Abnormal autophagic response contributes to cardiac dysfunction in diabetic rat hearts following pressure overload

The Faseb Journal, Apr 1, 2009

Research paper thumbnail of Acute effects of increased hexosamine biosynthesis and protein O-GlcNAcylation on cardiac gene expression

The Faseb Journal, Apr 1, 2010

Research paper thumbnail of Impaired cardiomyocyte autophagy in diabetes is associated with increased hexosamine biosynthesis and protein O-GlcNAc levels

The Faseb Journal, Apr 1, 2009

Research paper thumbnail of O-Glycosylation is Increased in the Tubuli and Glomeruli of Patients with Diabetic Nephropathy

The Faseb Journal, Apr 1, 2008

Research paper thumbnail of Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation

American Journal of Physiology Endocrinology and Metabolism, Aug 1, 1999

The aim of this study was to investigate the effect of increasing exogenous palmitate concentrati... more The aim of this study was to investigate the effect of increasing exogenous palmitate concentration on carbohydrate and palmitate oxidation in hearts from control and 1-wk diabetic rats. Hearts were perfused with glucose, [3-(13)C]lactate, and [U-(13)C]palmitate. Substrate oxidation rates were determined by combining (13)C-NMR glutamate isotopomer analysis of tissue extracts with measurements of oxygen consumption. Carbohydrate oxidation was markedly depressed after diabetes in the presence of low (0.1 mM) but not high (1.0 mM) palmitate concentration. Increasing exogenous palmitate concentration 10-fold resulted in a 7-fold increase in the contribution of palmitate to energy production in controls but only a 30% increase in the diabetic group. Consequently, at 0.1 mM palmitate, the rate of fatty acid oxidation was higher in the diabetic group than in controls; however, at 1.0 mM fatty acid oxidation, it was significantly depressed. Therefore, after 1 wk of diabetes, the major differences in carbohydrate and fatty acid metabolism occur primarily at low rather than high exogenous palmitate concentration.

Research paper thumbnail of Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

American Journal of Physiology Heart and Circulatory Physiology, Jul 1, 2004

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myo... more Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used (1)H and (13)C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and (13)C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a approximately 50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and approximately 30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia.

Research paper thumbnail of Peroxisome Proliferator-Activated Receptor Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart