CIDeRplusGeneral Information:
| Id: | 6,523 |
| Diseases: |
Cardiomyopathy, diabetic
Diabetes mellitus, type II - [OMIM] Insulin resistance |
| Mammalia | |
| review | |
| Reference: | Zou MH and Wu Y(2008) AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function Clin. Exp. Pharmacol. Physiol. 35: 535-545 [PMID: 18177481] |
Interaction Information:
| Comment | Increases in the ratio of AMP to ATP activate AMPK by a number of mechanisms, including direct allosteric activation and covalent modification due to activation by an AMP-dependent AMPK kinase (AMPKK), which phosphorylates the a-subunit on Thr172. |
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Formal Description Interaction-ID: 62060 |
phenotype increased intracellular AMP/ATP ratio increases_activity of complex/PPI AMPK |
| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62162 |
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| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62163 |
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| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62164 |
gene/protein CAMKK increases_activity of complex/PPI AMPK |
| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62165 |
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| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62166 |
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| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62167 |
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| Comment | AMP binds to AMPK and this makes it more susceptible to phosphorylation by an AMP-dependent AMPK kinase (AMPKK). The first AMPKK that has been identified is LKB1, a tumour suppressor that is mutated in humans with Peutz‚ÄďJegher syndrome, a disorder associated with an increased risk of developing carcinomas of the colon, stomach and pancreas. A second AMPKK has been identified as calcium calmodulin-dependent kinase kinase (CaMKK). |
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Formal Description Interaction-ID: 62168 |
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| Comment | AMPK is ubiquitous in distribution and its activity increases in a variety of cells in response to stressors such as hypoxia, oxidant stress, hyperosmolarity and, in muscle, exercise. |
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Formal Description Interaction-ID: 62169 |
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| Comment | AMPK is ubiquitous in distribution and its activity increases in a variety of cells in response to stressors such as hypoxia, oxidant stress, hyperosmolarity and, in muscle, exercise. |
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Formal Description Interaction-ID: 62170 |
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| Comment | AMPK is ubiquitous in distribution and its activity increases in a variety of cells in response to stressors such as hypoxia, oxidant stress, hyperosmolarity and, in muscle, exercise. |
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Formal Description Interaction-ID: 62171 |
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| Comment | AMPK is ubiquitous in distribution and its activity increases in a variety of cells in response to stressors such as hypoxia, oxidant stress, hyperosmolarity and, in muscle, exercise. |
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Formal Description Interaction-ID: 62172 |
environment exercise increases_activity of complex/PPI AMPK |
| Comment | AMPK may be regulated by cellular glycogen content, possibly as a consequence of AMPK binding to glycogen via its beta-subunit. |
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Formal Description Interaction-ID: 62173 |
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| Comment | Activation of AMPK leads to the phosphorylation of a number of target molecules that result in, among other things, increases in fatty acid oxidation and muscle glucose transport (to generate more ATP), as well as inhibition of various synthetic processes (to conserve ATP). |
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Formal Description Interaction-ID: 62174 |
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| Comment | Activation of AMPK leads to the phosphorylation of a number of target molecules that result in, among other things, increases in fatty acid oxidation and muscle glucose transport (to generate more ATP), as well as inhibition of various synthetic processes (to conserve ATP). |
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Formal Description Interaction-ID: 62175 |
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| Comment | Acetyl CoA carboxylase (ACC) and 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase were the first molecules shown to be AMPK targets. |
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Formal Description Interaction-ID: 62176 |
complex/PPI AMPK affects_activity of gene/protein ACAC |
| Comment | Acetyl CoA carboxylase (ACC) and 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase were the first molecules shown to be AMPK targets. |
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Formal Description Interaction-ID: 62177 |
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| Drugbank entries | Show/Hide entries for HMGCR |
| Comment | AMPK phosphorylates and activates malonyl CoA decarboxylase an enzyme involved in malonyl CoA turnover in many tissues, and it phosphorylates and inhibits glycerophosphate acyltransferase, the first committed enzyme in glycerolipid synthesis. |
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Formal Description Interaction-ID: 62178 |
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| Comment | AMPK phosphorylates and activates malonyl CoA decarboxylase an enzyme involved in malonyl CoA turnover in many tissues, and it phosphorylates and inhibits glycerophosphate acyltransferase, the first committed enzyme in glycerolipid synthesis. |
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Formal Description Interaction-ID: 62179 |
complex/PPI AMPK decreases_activity of gene/protein GPAT |
| Comment | Both endothelial and neuronal nitric oxide synthase (eNOS and nNOS, respectively) have been shown to be targets for AMPK in endothelium and muscle. |
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Formal Description Interaction-ID: 62180 |
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| Drugbank entries | Show/Hide entries for NOS3 |
| Comment | Both endothelial and neuronal nitric oxide synthase (eNOS and nNOS, respectively) have been shown to be targets for AMPK in endothelium and muscle. |
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Formal Description Interaction-ID: 62181 |
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| Drugbank entries | Show/Hide entries for NOS1 |
| Comment | Nicotine, via peroxynitrite (ONOO‚Äď), activates AMPK, resulting in enhanced threonine phosphorylation and consequent inhibition of FAS in 3T3L1 adipocytes. |
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Formal Description Interaction-ID: 62182 |
drug/chemical compound increases_activity of complex/PPI AMPK |
| Drugbank entries | Show/Hide entries for Nicotine |
| Comment | Nicotine, via peroxynitrite (ONOO‚Äď), activates AMPK, resulting in enhanced threonine phosphorylation and consequent inhibition of FAS in 3T3L1 adipocytes. |
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Formal Description Interaction-ID: 62183 |
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| Comment | Nicotine, via peroxynitrite (ONOO‚Äď), activates AMPK, resulting in enhanced threonine phosphorylation and consequent inhibition of FAS in 3T3L1 adipocytes. |
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Formal Description Interaction-ID: 62184 |
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| Drugbank entries | Show/Hide entries for FASN |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62185 |
phenotype increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62373 |
increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62374 |
increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62375 |
gene/protein increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62376 |
drug/chemical compound increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62377 |
drug/chemical compound increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62378 |
gene/protein increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62379 |
phenotype increases_activity of |
| Comment | The endothelium is a single layer of cells that covers the inner surface of all vessels in the body, including conduit vessels, resistance vessels, precapillary arterioles and capillaries. The endothelial layer forms a barrier between the elements of the blood and the tissues by virtue of its direct contact with the circulating blood. The intact function and structure of the endothelium are prerequisite for maintaining normal vascular function and anti-atherogenesis. The arterial wall endothelium has various important physiological functions, including adjusting vascular tone and permeability, antithrombosis and the secretion of diverse active materials. Arterial wall endothelium damage is an initiating factor for atherogenesis. The endothelium is susceptible to changes in blood elements, such as increases in blood glucose or free fatty acids (FFAs), angiotensin II, adrenaline, noradrenaline, bradykinin, as well as hypertension and hypercholesterolaemia. All these factors can cause vascular endothelium damage. |
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Formal Description Interaction-ID: 62380 |
phenotype increases_activity of |
| Comment | Endothelial dysfunction is characterized by increased superoxide production, impaired nitric oxide (NO) activity, increased endothelial apoptosis and a reduction in endothelium-dependent vasodilation. Chronic dysfunction of the endothelium is implicated in the pathophysiology of several cardiovascular disorders, including atherosclerosis, hypertension, diabetic vasculopathy and heart failure. |
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Formal Description Interaction-ID: 62381 |
increases_activity of process |
| Comment | Endothelial dysfunction is characterized by increased superoxide production, impaired nitric oxide (NO) activity, increased endothelial apoptosis and a reduction in endothelium-dependent vasodilation. Chronic dysfunction of the endothelium is implicated in the pathophysiology of several cardiovascular disorders, including atherosclerosis, hypertension, diabetic vasculopathy and heart failure. |
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Formal Description Interaction-ID: 62382 |
affects_activity of drug/chemical compound |
| Comment | Endothelial dysfunction is characterized by increased superoxide production, impaired nitric oxide (NO) activity, increased endothelial apoptosis and a reduction in endothelium-dependent vasodilation. Chronic dysfunction of the endothelium is implicated in the pathophysiology of several cardiovascular disorders, including atherosclerosis, hypertension, diabetic vasculopathy and heart failure. |
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Formal Description Interaction-ID: 62383 |
increases_activity of process endothelial cell apoptotic process |
| Comment | Endothelial dysfunction is characterized by increased superoxide production, impaired nitric oxide (NO) activity, increased endothelial apoptosis and a reduction in endothelium-dependent vasodilation. Chronic dysfunction of the endothelium is implicated in the pathophysiology of several cardiovascular disorders, including atherosclerosis, hypertension, diabetic vasculopathy and heart failure. |
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Formal Description Interaction-ID: 62384 |
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| Comment | AMPK is a heterotrimeric protein consisting of three subunits, alpha, beta, and gamma, each of which has at least two isoforms that can lead to the formation of 12 different complexes. These combinations render AMPK complexes with different properties and relative tissue specificity. The alpha-subunit contains the catalytic site, whereas the beta- and gamma-regulatory subunits are important in maintaining the stability of the heterotrimer complex. However, all subunits are necessary for full activity. Different tissues express distinct alpha-catalytic subunits that account for the major part of AMPK activity. Muscle cells mainly express AMPK complexes containing the alpha2-subunit and adipocytes express the alpha1 isoform. The liver expresses both alpha1 and alpha2 isoforms. |
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Formal Description Interaction-ID: 62385 |
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| Comment | AMPK is a heterotrimeric protein consisting of three subunits, alpha, beta, and gamma, each of which has at least two isoforms that can lead to the formation of 12 different complexes. These combinations render AMPK complexes with different properties and relative tissue specificity. The alpha-subunit contains the catalytic site, whereas the beta- and gamma-regulatory subunits are important in maintaining the stability of the heterotrimer complex. However, all subunits are necessary for full activity. Different tissues express distinct alpha-catalytic subunits that account for the major part of AMPK activity. Muscle cells mainly express AMPK complexes containing the alpha2-subunit and adipocytes express the alpha1 isoform. The liver expresses both alpha1 and alpha2 isoforms. |
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Formal Description Interaction-ID: 62388 |
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| Comment | AMPK is a heterotrimeric protein consisting of three subunits, alpha, beta, and gamma, each of which has at least two isoforms that can lead to the formation of 12 different complexes. These combinations render AMPK complexes with different properties and relative tissue specificity. The alpha-subunit contains the catalytic site, whereas the beta- and gamma-regulatory subunits are important in maintaining the stability of the heterotrimer complex. However, all subunits are necessary for full activity. Different tissues express distinct alpha-catalytic subunits that account for the major part of AMPK activity. Muscle cells mainly express AMPK complexes containing the alpha2-subunit and adipocytes express the alpha1 isoform. The liver expresses both alpha1 and alpha2 isoforms. |
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Formal Description Interaction-ID: 62389 |
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| Drugbank entries | Show/Hide entries for PRKAA1 |
| Comment | AMPK is a heterotrimeric protein consisting of three subunits, alpha, beta, and gamma, each of which has at least two isoforms that can lead to the formation of 12 different complexes. These combinations render AMPK complexes with different properties and relative tissue specificity. The alpha-subunit contains the catalytic site, whereas the beta- and gamma-regulatory subunits are important in maintaining the stability of the heterotrimer complex. However, all subunits are necessary for full activity. Different tissues express distinct alpha-catalytic subunits that account for the major part of AMPK activity. Muscle cells mainly express AMPK complexes containing the alpha2-subunit and adipocytes express the alpha1 isoform. The liver expresses both alpha1 and alpha2 isoforms. |
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Formal Description Interaction-ID: 62390 |
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| Drugbank entries | Show/Hide entries for PRKAA1 |
| Comment | AMPK is expressed in both endothelial cells and smooth muscle cells. Both alpha1- and alpha2-catalytic subunits are expressed in arterial smooth muscle cells, although their relative proportion differs between different arteries. Both alpha1- and alpha2-catalytic subunits are expressed in endothelial cells and the predominant isoform is alpha1. Although the AMPKalpha2 isoform is barely detectable in endothelial cells, it still has important physiological functions; for example, it is essential for angiogenesis in response to hypoxic stress. The functional significance of these different combinations remains unclear; however, it is noted that AMPK complexes containing the alpha1 isoform are less sensitive to AMP. |
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Formal Description Interaction-ID: 62391 |
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| Drugbank entries | Show/Hide entries for PRKAA1 |
| Comment | AMPK is expressed in both endothelial cells and smooth muscle cells. Both alpha1- and alpha2-catalytic subunits are expressed in arterial smooth muscle cells, although their relative proportion differs between different arteries. Both alpha1- and alpha2-catalytic subunits are expressed in endothelial cells and the predominant isoform is alpha1. Although the AMPKalpha2 isoform is barely detectable in endothelial cells, it still has important physiological functions; for example, it is essential for angiogenesis in response to hypoxic stress. The functional significance of these different combinations remains unclear; however, it is noted that AMPK complexes containing the alpha1 isoform are less sensitive to AMP. |
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Formal Description Interaction-ID: 62393 |
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| Comment | AMPK is expressed in both endothelial cells and smooth muscle cells. Both alpha1- and alpha2-catalytic subunits are expressed in arterial smooth muscle cells, although their relative proportion differs between different arteries. Both alpha1- and alpha2-catalytic subunits are expressed in endothelial cells and the predominant isoform is alpha1. Although the AMPKalpha2 isoform is barely detectable in endothelial cells, it still has important physiological functions; for example, it is essential for angiogenesis in response to hypoxic stress. The functional significance of these different combinations remains unclear; however, it is noted that AMPK complexes containing the alpha1 isoform are less sensitive to AMP. |
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Formal Description Interaction-ID: 62395 |
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| Drugbank entries | Show/Hide entries for PRKAA1 |
| Comment | AMPK is expressed in both endothelial cells and smooth muscle cells. Both alpha1- and alpha2-catalytic subunits are expressed in arterial smooth muscle cells, although their relative proportion differs between different arteries. Both alpha1- and alpha2-catalytic subunits are expressed in endothelial cells and the predominant isoform is alpha1. Although the AMPKalpha2 isoform is barely detectable in endothelial cells, it still has important physiological functions; for example, it is essential for angiogenesis in response to hypoxic stress. The functional significance of these different combinations remains unclear; however, it is noted that AMPK complexes containing the alpha1 isoform are less sensitive to AMP. |
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Formal Description Interaction-ID: 62396 |
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| Comment | In endothelial cells, AMPK is activated by two AMPKK pathways, LKB1 and CaMKKbeta. Several direct and indirect arguments suggest that LKB1 is involved in AMPK activation in endothelial cells. Treatment of endothelial cells with AICAR, a drug that is transformed in the cell into 5-amino-4-imidazolecarboxamide (AICA)-riboside (also termed ‚ÄėZMP‚Äô), an analogue of AMP, activates AMPK in endothelial cells. ONOO- and hypoxia-reoxygenation activate AMPK by stimulating LKB1 phosphorylation at Ser428. Furthermore, direct mutation of Ser428 of LKB1 into alanine and the kinase-inactive LKB1 mutant abolished ONOO- induced AMPK activation. A study of human endothelial cells showed that AMPK is activated by thrombin through a Ca2+-dependent mechanism. Inhibition of CaMKK with STO-609 or downregulation of CaMKKbeta using RNA interference decreased thrombin-induced AMPK activation significantly, indicating that CaMKKbeta was the responsible AMPK kinase. |
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Formal Description Interaction-ID: 62399 |
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| Comment | In endothelial cells, AMPK is activated by two AMPKK pathways, LKB1 and CaMKKbeta. Several direct and indirect arguments suggest that LKB1 is involved in AMPK activation in endothelial cells. Treatment of endothelial cells with AICAR, a drug that is transformed in the cell into 5-amino-4-imidazolecarboxamide (AICA)-riboside (also termed ‚ÄėZMP‚Äô), an analogue of AMP, activates AMPK in endothelial cells. ONOO- and hypoxia-reoxygenation activate AMPK by stimulating LKB1 phosphorylation at Ser428. Furthermore, direct mutation of Ser428 of LKB1 into alanine and the kinase-inactive LKB1 mutant abolished ONOO- induced AMPK activation. A study of human endothelial cells showed that AMPK is activated by thrombin through a Ca2+-dependent mechanism. Inhibition of CaMKK with STO-609 or downregulation of CaMKKbeta using RNA interference decreased thrombin-induced AMPK activation significantly, indicating that CaMKKbeta was the responsible AMPK kinase. |
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Formal Description Interaction-ID: 62402 |
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| Comment | Recent studies have demonstrated that prolonged exposure of endothelial cells to palmitate significantly suppresses the phosphorylation of AMPK and its downstream enzyme ACC. Studies have provided compelling evidence obtained in vitro and in vivo that palmitate inhibits both AMPK and eNOS phosphorylation by ceramide-dependent protein phosphatase 2A (PP2A) activation. This observation provides support for the concept that PP2A is an important component for the dephosphorylation and inactivaton of AMPK and may directly modulate AMPK function. In support of this idea, it has been reported that the PP2A complex is involved in regulating the interaction between AMPK alpha2 and gamma1 and inactivation of AMPK in pancreatic beta-cells, and that the active phosphorylated form of AMPK can be inactivated in cell-free assays by PP2A. |
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Formal Description Interaction-ID: 62404 |
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| Drugbank entries | Show/Hide entries for Palmitic acid |
| Comment | Recent studies have demonstrated that prolonged exposure of endothelial cells to palmitate significantly suppresses the phosphorylation of AMPK and its downstream enzyme ACC. Studies have provided compelling evidence obtained in vitro and in vivo that palmitate inhibits both AMPK and eNOS phosphorylation by ceramide-dependent protein phosphatase 2A (PP2A) activation. This observation provides support for the concept that PP2A is an important component for the dephosphorylation and inactivaton of AMPK and may directly modulate AMPK function. In support of this idea, it has been reported that the PP2A complex is involved in regulating the interaction between AMPK alpha2 and gamma1 and inactivation of AMPK in pancreatic beta-cells, and that the active phosphorylated form of AMPK can be inactivated in cell-free assays by PP2A. |
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Formal Description Interaction-ID: 62408 |
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| Drugbank entries | Show/Hide entries for Palmitic acid or NOS3 |
| Comment | Recent studies have demonstrated that prolonged exposure of endothelial cells to palmitate significantly suppresses the phosphorylation of AMPK and its downstream enzyme ACC. Studies have provided compelling evidence obtained in vitro and in vivo that palmitate inhibits both AMPK and eNOS phosphorylation by ceramide-dependent protein phosphatase 2A (PP2A) activation. This observation provides support for the concept that PP2A is an important component for the dephosphorylation and inactivaton of AMPK and may directly modulate AMPK function. In support of this idea, it has been reported that the PP2A complex is involved in regulating the interaction between AMPK alpha2 and gamma1 and inactivation of AMPK in pancreatic beta-cells, and that the active phosphorylated form of AMPK can be inactivated in cell-free assays by PP2A. |
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Formal Description Interaction-ID: 62411 |
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| Drugbank entries | Show/Hide entries for Palmitic acid |
| Comment | Recent studies have demonstrated that prolonged exposure of endothelial cells to palmitate significantly suppresses the phosphorylation of AMPK and its downstream enzyme ACC. Studies have provided compelling evidence obtained in vitro and in vivo that palmitate inhibits both AMPK and eNOS phosphorylation by ceramide-dependent protein phosphatase 2A (PP2A) activation. This observation provides support for the concept that PP2A is an important component for the dephosphorylation and inactivaton of AMPK and may directly modulate AMPK function. In support of this idea, it has been reported that the PP2A complex is involved in regulating the interaction between AMPK alpha2 and gamma1 and inactivation of AMPK in pancreatic beta-cells, and that the active phosphorylated form of AMPK can be inactivated in cell-free assays by PP2A. |
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Formal Description Interaction-ID: 62413 |
complex/PPI Protein phosphatase 2A decreases_activity of complex/PPI AMPK |
| Comment | Recent studies have demonstrated that prolonged exposure of endothelial cells to palmitate significantly suppresses the phosphorylation of AMPK and its downstream enzyme ACC. Studies have provided compelling evidence obtained in vitro and in vivo that palmitate inhibits both AMPK and eNOS phosphorylation by ceramide-dependent protein phosphatase 2A (PP2A) activation. This observation provides support for the concept that PP2A is an important component for the dephosphorylation and inactivaton of AMPK and may directly modulate AMPK function. In support of this idea, it has been reported that the PP2A complex is involved in regulating the interaction between AMPK alpha2 and gamma1 and inactivation of AMPK in pancreatic beta-cells, and that the active phosphorylated form of AMPK can be inactivated in cell-free assays by PP2A. |
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Formal Description Interaction-ID: 62414 |
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| Drugbank entries | Show/Hide entries for NOS3 |
| Comment | PP2A is a multimeric ubiquitously expressed serine/threonine phosphatase consisting of scaffolding A, regulatory B and catalytic C subunits. PP2A has been shown to be ceramide responsive in vitro and in vivo and is also termed ‚Äėceramide-activated protein phosphatase‚Äô (CAPP). In contrast with PP2C, endothelial cells have abundant PP2A expression. Increasing evidence indicates that PP2A plays important roles in maintaining endothelial cell physiological functions, including regulation of endothelial cell cytoskeletal structure, protection of the endothelial cell barrier, maintenance of endothelial cells in a resting state and limiting the motility that is needed for the morphogenic process of angiogenesis. Moreover, PP2A can regulate eNOS phosphorylation status directly by dephosphorylating serine 1177/1179. However, excessive PP2A activation in pathological conditions results in endothelial cell damage or dysfunction by inhibition of AMPK activity. |
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Formal Description Interaction-ID: 62416 |
drug/chemical compound Ceramide increases_activity of complex/PPI Protein phosphatase 2A |
| Comment | PP2A is a multimeric ubiquitously expressed serine/threonine phosphatase consisting of scaffolding A, regulatory B and catalytic C subunits. PP2A has been shown to be ceramide responsive in vitro and in vivo and is also termed ‚Äėceramide-activated protein phosphatase‚Äô (CAPP). In contrast with PP2C, endothelial cells have abundant PP2A expression. Increasing evidence indicates that PP2A plays important roles in maintaining endothelial cell physiological functions, including regulation of endothelial cell cytoskeletal structure, protection of the endothelial cell barrier, maintenance of endothelial cells in a resting state and limiting the motility that is needed for the morphogenic process of angiogenesis. Moreover, PP2A can regulate eNOS phosphorylation status directly by dephosphorylating serine 1177/1179. However, excessive PP2A activation in pathological conditions results in endothelial cell damage or dysfunction by inhibition of AMPK activity. |
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Formal Description Interaction-ID: 62419 |
complex/PPI Protein phosphatase 2A affects_activity of |
| Comment | Reactive nitrogen species (RNS) are derived from NO. Of these, peroxynitrite (ONOO-) is the best characterized and appears to have the most biological activity. Peroxynitrite is formed by the biradical reaction of NO and O2-. Many oxidation and nitration products are produced from the reaction of ONOO- with cellular macromolecules. Cells exposed to oxidants such as ONOO- and H2O2 activate AMPK, although the mechanism remains to be determined. ONOO- activated AMPK in endothelial cells and increased the phosphorylation of its down-stream enzymes eNOS-Ser and ACC-Ser. |
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Formal Description Interaction-ID: 62420 |
drug/chemical compound Reactive nitrogen species increases_activity of complex/PPI AMPK |
| Comment | A major weapon of endothelial cells to fight vascular diseases is eNOS, an enzyme that generates the vasoprotective molecule NO which requires Ca 2+/calmodulin, flavin adenine dinucleotide, flavin mononucleotide and tetrahydrobiopterin (BH4) as cofactors. Vascular NO has a variety of functions, but its most important action is to dilate all types of blood vessels and maintain vascular homeostasis by stimulating soluble guanylyl cyclase and increasing cGMP in smooth muscle cells. |
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Formal Description Interaction-ID: 62426 |
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| Drugbank entries | Show/Hide entries for NOS3 |
| Comment | A major weapon of endothelial cells to fight vascular diseases is eNOS, an enzyme that generates the vasoprotective molecule NO which requires Ca 2+/calmodulin, flavin adenine dinucleotide, flavin mononucleotide and tetrahydrobiopterin (BH4) as cofactors. Vascular NO has a variety of functions, but its most important action is to dilate all types of blood vessels and maintain vascular homeostasis by stimulating soluble guanylyl cyclase and increasing cGMP in smooth muscle cells. |
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Formal Description Interaction-ID: 62429 |
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| Comment | A major weapon of endothelial cells to fight vascular diseases is eNOS, an enzyme that generates the vasoprotective molecule NO which requires Ca 2+/calmodulin, flavin adenine dinucleotide, flavin mononucleotide and tetrahydrobiopterin (BH4) as cofactors. Vascular NO has a variety of functions, but its most important action is to dilate all types of blood vessels and maintain vascular homeostasis by stimulating soluble guanylyl cyclase and increasing cGMP in smooth muscle cells. |
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Formal Description Interaction-ID: 62435 |
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| Comment | A major weapon of endothelial cells to fight vascular diseases is eNOS, an enzyme that generates the vasoprotective molecule NO which requires Ca 2+/calmodulin, flavin adenine dinucleotide, flavin mononucleotide and tetrahydrobiopterin (BH4) as cofactors. Vascular NO has a variety of functions, but its most important action is to dilate all types of blood vessels and maintain vascular homeostasis by stimulating soluble guanylyl cyclase and increasing cGMP in smooth muscle cells. |
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Formal Description Interaction-ID: 62436 |
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| Comment | NO has been shown to inhibit DNA synthesis, mitogenesis and proliferation of vascular smooth muscle cells, which are important components of vessel wall remodelling during atherosclerosis formation. |
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Formal Description Interaction-ID: 62438 |
drug/chemical compound decreases_activity of process |
| Comment | NO has been shown to inhibit DNA synthesis, mitogenesis and proliferation of vascular smooth muscle cells, which are important components of vessel wall remodelling during atherosclerosis formation. |
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Formal Description Interaction-ID: 62439 |
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| Comment | NO suppresses smooth muscle exposure to platelet-derived growth factor(s) by inhibiting platelet aggregation and adhesion. Thus, NO prevents the formation of fibrous plaque, a later step in atherogenesis. |
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Formal Description Interaction-ID: 62440 |
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| Comment | As in muscle cells, endothelial AMPK has been shown to phosphorylate and inhibit ACC activity; this leads to a reduction in malonyl-CoA, which, in turn, disinhibits carnitine palmitoyltransferase and accelerates mitochondrial FFA oxidation. |
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Formal Description Interaction-ID: 62441 |
complex/PPI AMPK decreases_activity of gene/protein ACAC |
| Comment | As in muscle cells, endothelial AMPK has been shown to phosphorylate and inhibit ACC activity; this leads to a reduction in malonyl-CoA, which, in turn, disinhibits carnitine palmitoyltransferase and accelerates mitochondrial FFA oxidation. |
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Formal Description Interaction-ID: 62442 |
complex/PPI AMPK decreases_quantity of drug/chemical compound |
| Comment | As in muscle cells, endothelial AMPK has been shown to phosphorylate and inhibit ACC activity; this leads to a reduction in malonyl-CoA, which, in turn, disinhibits carnitine palmitoyltransferase and accelerates mitochondrial FFA oxidation. |
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Formal Description Interaction-ID: 62443 |
complex/PPI AMPK increases_activity of gene/protein CPT |
| Comment | As in muscle cells, endothelial AMPK has been shown to phosphorylate and inhibit ACC activity; this leads to a reduction in malonyl-CoA, which, in turn, disinhibits carnitine palmitoyltransferase and accelerates mitochondrial FFA oxidation. |
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Formal Description Interaction-ID: 62444 |
complex/PPI AMPK increases_activity of process |
| Comment | The hormone adiponectin, which can decrease lipid accumulation in non-adipose tissues, is known to activate endothelial AMPK via a membrane receptor. |
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Formal Description Interaction-ID: 62445 |
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