Abstract 12309: Histamine Receptor 2 Activation Worsens Myocardial Ischemia/Reperfusion Injury via Inducing Mitochondrial and Endothelial Dysfunction
Background: Although clinical and experimental evidence indicates that histamine receptor 2 (H2R) blockade improves both chronic heart failure and myocardial ischemia/reperfusion (I/R) injury, the underlying cellular mechanisms are not fully understood. Histamine is known to increase vascular permeability and induce cell apoptosis, which are closely associated with endothelial and mitochondrial dysfunction, respectively, while it is believed that mitochondrial and endothelial functions are crucial in I/R injury. Here we hypothesized that H2R activation worsens I/R injury by increasing the mitochondrial and endothelial permeability.
Methods and Results: In neonatal rat cardiomyocytes, histamine dose-dependently reduced cell viability and induced cell apoptosis detected by MTT and Hoechst staining, respectively. The protein levels of p-ERK1/2, bax, p-DAPK2 and caspase 3 were increased by H2R agonists. Mito-tracker and calcein plus CoCl2 assay showed that either histamine or H2R selective agonist, amthamine dihydrobromide (AD), markedly increased mitochondrial permeability. In the cultured HUVECs, either histamine or AD increased the protein levels of p-ERK1/2 and p-moesin, while the endothelial permeability during anoxia/reoxygenation determined by transcellular electrical resistance was enhanced by either histamine or AD treatment. All of those effects were blocked by a H2R blocker, famotidine or an ERK inhibitor, U0126. In response to myocardial I/R (45 min/24 h) or ischemia for 24 h in C57 mice, the infarct size was reduced by the treatment with famotidine or CsA (mPTP inhibitor), whereas AD increased infarct size. In H2R KO mice, the infarct size was smaller than in WT mice and CsA further reduced it. Moreover, either famotidine or gene deficiency of H2R decreased the infiltration of nurtrophils into myocardium detected by myeloperoxidase immunostaining.
Conclusion: We provided first evidence that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and consequently inducing cell apoptosis as well as by increasing myocardial vascular endothelial permeability. Our findings hint that H2R blockade is a new therapeutic approach for myocardial I/R injury.
- © 2012 by American Heart Association, Inc.