Abstract
There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the histamine H2 receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angina Pectoris / blood
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Case-Control Studies
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Caspase 3 / metabolism
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Cell Membrane Permeability
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Cells, Cultured
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Death-Associated Protein Kinases
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Dose-Response Relationship, Drug
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Histamine / blood
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Histamine / metabolism*
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Histamine / pharmacology
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Histamine Agonists / pharmacology
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Histamine H2 Antagonists / pharmacology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism*
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Human Umbilical Vein Endothelial Cells / pathology
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Humans
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Mice
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Mice, Knockout
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Microfilament Proteins / metabolism
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Mitochondria, Heart / drug effects
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Mitochondria, Heart / metabolism*
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Mitochondria, Heart / pathology
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Mitochondrial Membranes / metabolism
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Myocardial Infarction / genetics
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Myocardial Infarction / metabolism*
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Myocardial Infarction / pathology
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Myocardial Infarction / prevention & control
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Myocardial Reperfusion Injury / genetics
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Myocardial Reperfusion Injury / metabolism*
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Myocardial Reperfusion Injury / pathology
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Myocardial Reperfusion Injury / prevention & control
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Permeability
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Receptors, Histamine H2 / deficiency
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Receptors, Histamine H2 / drug effects*
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Receptors, Histamine H2 / genetics
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Receptors, Histamine H2 / metabolism
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Time Factors
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Bax protein, mouse
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Histamine Agonists
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Histamine H2 Antagonists
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Microfilament Proteins
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Protein Kinase Inhibitors
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Receptors, Histamine H2
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bcl-2-Associated X Protein
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moesin
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Histamine
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DAPK2 protein, human
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Death-Associated Protein Kinases
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dapk2 protein, mouse
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Calcium-Calmodulin-Dependent Protein Kinases
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Extracellular Signal-Regulated MAP Kinases
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Casp3 protein, mouse
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Caspase 3