title: Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function.
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.
authors: Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, 510515, Guangzhou, China.
authors: Tao
authors: T
authors: Luo
authors: Baihe
authors: B
authors: Chen
authors: Zonglei
authors: Z
authors: Zhao
authors: Nvqin
authors: N
authors: He
authors: Zhi
authors: Z
authors: Zeng
authors: Bing
authors: B
authors: Wu
authors: Yasushi
authors: Y
authors: Fukushima
authors: Meng
authors: M
authors: Dai
authors: Qiaobing
authors: Q
authors: Huang
authors: Dingli
authors: D
authors: Xu
authors: Jianping
authors: J
authors: Bin
authors: Masafumi
authors: M
authors: Kitakaze
authors: Yulin
authors: Y
authors: Liao
mesh_terms: D000787:Angina Pectoris / Q000097:blood; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006632:Histamine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010539:Permeability; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; D017442:Histamine Agonists; D006635:Histamine H2 Antagonists; D008840:Microfilament Proteins; D047428:Protein Kinase Inhibitors; D011970:Receptors, Histamine H2; D051028:bcl-2-Associated X Protein; C071058:moesin; D006632:Histamine; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; C579103:dapk2 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3