Abstract 88: AMP-activated Protein Kinase Signaling Mediates the Cardioprotective effect of Antithrombin against Myocardial Ischemia and Reperfusion Injury

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ji Li ◽  
Yina Ma ◽  
Jinli Wang ◽  
Hui Yang ◽  
Yanqing Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Coagulation System ◽  
Acid Oxidation ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Substrate Metabolism ◽  
High Affinity ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Background: Antithrombin (AT) is an endogenous protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to distinct heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells. The energy sensor AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischemia and reperfusion (I/R). The objective of this study was to investigate whether the cardioprotective signaling function of AT against I/R injury is mediated through the AMPK pathway. Methods and Results: The cardioprotective activities of wild-type (WT) AT and its two recombinant derivatives, one having high affinity and the other no affinity for heparin, were evaluated in an acute I/R (20 min/4 h) injury model in which the left anterior descending coronary artery (LAD) was occluded. The serpin derivatives were given 5 min before reperfusion. The results showed that AT-WT can activate the protective AMPK signaling pathway in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK, but the derivative lacking any affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. The activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity of AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. Conclusions: These results suggest that AT binds to vascular HSPGs to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.

Abstract 11738: AMP-Activated Protein Kinase Signaling Mediates the Cardioprotective Effect of Antithrombin Against Myocardial Ischemia and Reperfusion Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yina Ma ◽  
Jinli Wang ◽  
Junjie Gao ◽  
Hui Yang ◽  
Wanqing Sun ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ex Vivo ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Substrate Metabolism ◽  
High Affinity ◽  
Heparin Sulfate ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Introduction: Antithrombin (AT) is an endogenous protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. In addition to its anticoagulant function, AT also exhibits an anti-inflammatory and cardioprotective function when it binds to distinct heparin sulfate proteoglycans (HSPG) on vascular endothelial cells. The energy sensor AMP-activated protein kinase (AMPK) is known to play an important cardioprotective role during myocardial ischemia and reperfusion (I/R). Hypothesis: The cardioprotective function of AT may be through activation of AMPK by which modulates the substrate metabolism. Methods: The cardioprotective activities of wild-type (WT) AT and its two recombinant derivatives one having high affinity and the other no affinity for heparin were evaluated in an acute in vivo regional ischemia/reperfusion (30 min/24 hours) injury model in which the left anterior descending coronary artery (LAD) was occluded and released. The serpin derivatives were given 5 min before reperfusion. Langendroff perfused heart system was used to approach an ex vivo global ischemia model. Results: AT-WT can activate the protective AMPK signaling pathway in both in vivo and ex vivo conditions. Blocking AMPK activity by using AMPK kinase dead (KD) transgenic mice, the cardioprotective function of AT against I/R damage was abolished. The AT derivative having high affinity for heparin was more effective in activating AMPK but the derivative lacking any affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Moreover, the AMPK-dependent activity of AT significantly inhibited I/R-induced inflammatory c-Jun N-terminal protein kinase (JNK) pathway. In the ex vivo working heart perfusion system, the further studies revealed that the AMPK activity of AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. Conclusions: These results suggest that AT binds to heparin sulfate proteoglycans to invoke a cardioprotective function through triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.

scholarly journals Antithrombin up-regulates AMP-activated protein kinase signalling during myocardial ischaemia/reperfusion injury

2015 ◽  
Vol 113 (02) ◽  
pp. 338-349 ◽  
Author(s):  
Yina Ma ◽  
Jinli Wang ◽  
Junjie Gao ◽  
Hui Yang ◽  
Yanqing Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischaemia ◽  
Ex Vivo ◽  
Coagulation System ◽  
Acid Oxidation ◽  
Ischaemia Reperfusion Injury ◽  
Substrate Metabolism ◽  
High Affinity ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

SummaryAntithrombin (AT) is a protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to heparan sulfate proteo - glycans (HSPGs) on vascular cells. AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischaemia and reperfusion (I/R). To determine whether the cardioprotective signaling function of AT is mediated through the AMPK pathway, we evaluated the cardioprotective activities of wild-type AT and its two derivatives, one having high affinity and the other no affinity for heparin, in an acute I/R injury model in C57BL/6J mice in which the left anterior descending coronary artery was occluded. The serpin derivatives were given 5 minutes before reperfusion. The results showed that AT-WT can activate AMPK in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK and in limiting infraction, but the derivative lacking affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity induced by AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. These results suggest that AT binds to HSPGs on heart tissues to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signalling pathways and modulating substrate metabolism during I/R.

scholarly journals Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion

2006 ◽  
Vol 101 (2) ◽  
pp. 576-582 ◽  
Author(s):  
Stephen J. Crozier ◽  
Xueqian Zhang ◽  
Jufang Wang ◽  
Joseph Cheung ◽  
Scot R. Kimball ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Protein Expression ◽  
Signaling Pathways ◽  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Mechanisms ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Mitogen Activated Protein

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.

AMP-activated protein kinase regulation and action in skeletal muscle during exercise

2003 ◽  
Vol 31 (1) ◽  
pp. 191-195 ◽  
Author(s):  
N. Musi ◽  
H. Yu ◽  
L.J. Goodyear
Keyword(s):  
Protein Kinase ◽  
Exercise Training ◽  
Metabolic Pathways ◽  
Acute Exercise ◽  
Glycogen Content ◽  
Glycogen Metabolism ◽  
Acid Oxidation ◽  
Ampk Activity ◽  
Energy Sensing ◽  
Amp Activated Protein Kinase

Physical exercise increases muscle glucose uptake, enhances insulin sensitivity and leads to fatty acid oxidation in muscle. The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is strongly activated during muscle contraction due to acute decreases in ATP/AMP and phosphocreatine/creatine ratios. Accumulating evidence suggests that AMPK plays an important role in mediating these metabolic processes. Furthermore, AMPK has been implicated in regulating gene transcription and therefore may play a role in some of the cellular adaptations to training exercise. There is also evidence that changes in AMPK activity result in altered cellular glycogen content, suggesting that this enzyme regulates glycogen metabolism. Recent studies have shown that the magnitude of AMPK activation and associated metabolic responses are affected by factors such as glycogen content, exercise training and fibre type. In summary, AMPK regulates several metabolic pathways during acute exercise and modifies the expression of many genes involved in the adaptive changes to exercise training.

Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

2009 ◽  
Vol 297 (1) ◽  
pp. H313-H321 ◽  
Author(s):  
Clifford D. L. Folmes ◽  
Cory S. Wagg ◽  
Mei Shen ◽  
Alexander S. Clanachan ◽  
Rong Tian ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Functional Recovery ◽  
Recovery Of Function ◽  
High Energy ◽  
Acid Oxidation ◽  
Protein Kinase Activity ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Activation of 5′-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) α2-subunit of AMPK (AMPK-α2 DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-14C]glucose, 0.4 mM [9, 10-3H]palmitate, and 100 μU/ml insulin. AMPK-α2 DN hearts had reduced AMPK activity at the end of reperfusion (82 ± 9 vs. 141 ± 7 pmol·mg−1·min−1) with no changes in high-energy phosphates. Despite this, AMPK-α2 DN hearts had improved recovery of function during reperfusion (14.9 ± 0.8 vs. 9.4 ± 1.4 beats·min−1·mmHg·10−3). During reperfusion, fatty acid oxidation provided 44.0 ± 2.8% of total acetyl-CoA in AMPK-α2 DN hearts compared with 55.0 ± 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 ± 9.4% vs. 85.3 ± 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.

scholarly journals Regulation of glucose transport by the AMP-activated protein kinase

2004 ◽  
Vol 63 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Nobuharu Fujii ◽  
William G. Aschenbach ◽  
Nicolas Musi ◽  
Michael F. Hirshman ◽  
Laurie J. Goodyear
Keyword(s):  
Protein Kinase ◽  
Glucose Transport ◽  
Glycogen Content ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Muscle Biology ◽  
Ampk Activity ◽  
Energy Sensing ◽  
Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated during exercise and muscle contraction as a result of acute decreases in ATP:AMP and phosphocreatine:creatine. Physical exercise increases muscle glucose uptake, enhances insulin sensitivity and leads to fatty acid oxidation in muscle. An important issue in muscle biology is to understand whether AMPK plays a role in mediating these metabolic processes. AMPK has also been implicated in regulating gene transcription and, therefore, may function in some of the cellular adaptations to training exercise. Recent studies have shown that the magnitude of AMPK activation and associated metabolic responses are affected by factors such as glycogen content, exercise training and fibre type. There have also been conflicting reports as to whether AMPK activity is necessary for contraction-stimulated glucose transport. Thus, during the next several years considerably more research will be necessary in order to fully understand the role of AMPK in regulating glucose transport in skeletal muscle.

Role of AMP-activated protein kinase in healthy and diseased hearts

2006 ◽  
Vol 291 (6) ◽  
pp. H2557-H2569 ◽  
Author(s):  
Vernon W. Dolinsky ◽  
Jason R. B. Dyck
Keyword(s):  
Energy Metabolism ◽  
Protein Kinase ◽  
Cardiac Myocyte ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Cardiac Energy Metabolism ◽  
Ampk Activity ◽  
Cardiac Energy ◽  
Metabolic Stresses ◽  
Amp Activated Protein Kinase

The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed.

Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power

2005 ◽  
Vol 289 (3) ◽  
pp. H1033-H1037 ◽  
Author(s):  
Kristen L. King ◽  
Isidore C. Okere ◽  
Naveen Sharma ◽  
Jason R. B. Dyck ◽  
Aneta E. Reszko ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Cardiac Power ◽  
Malonyl Coa ◽  
Ampk Activity ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Amp Activated Protein Kinase

Myocardial fatty acid oxidation is regulated by carnitine palmitoyltransferase I (CPT I), which is inhibited by malonyl-CoA. Increased cardiac power causes a fall in malonyl-CoA content and accelerated fatty acid oxidation; however, the mechanism for the decrease in malonyl-CoA is unclear. Malonyl-CoA is formed by acetyl-CoA carboxylase (ACC) and degraded by malonyl-CoA decarboxylase (MCD); thus a fall in malonyl-CoA could be due to activation of MCD, inhibition of ACC, or both. This study assessed the effects of increased cardiac power on malonyl-CoA content and ACC and MCD activities. Anesthetized pigs were studied under control conditions and during increased cardiac power in response to dobutamine infusion and aortic constriction alone, under hyperglycemic conditions, or with the CPT I inhibitor oxfenicine. An increase in cardiac power was accompanied by increased myocardial O2 consumption, decreased malonyl-CoA concentration, and increased fatty acid oxidation. There were no differences among groups in activity of ACC or AMP-activated protein kinase (AMPK), which physiologically inhibits ACC. There also were no differences in Vmax or Km of MCD. Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity. In conclusion, the fall in malonyl-CoA and increase in fatty acid oxidization that occur with increased cardiac work were not due to inhibition of ACC or activation of MCD, suggesting alternative regulatory mechanisms for the work-induced decrease in malonyl-CoA concentration.

Sign in / Sign up

Export Citation Format

Share Document