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Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function

  • Tao Luo
  • Baihe Chen
  • Zonglei Zhao
  • Nvqin He
  • Zhi Zeng
  • Bing Wu
  • Yasushi Fukushima
  • Meng Dai
  • Qiaobing Huang
  • Dingli Xu
  • Jianping Bin
  • Masafumi Kitakaze
  • Yulin LiaoEmail author
Original Contribution

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.

Keywords

Histamine H2 receptor Ischemia Ischemia/reperfusion Mitochondrial permeability Vascular permeability 

Notes

Acknowledgments

We thank Zhonghua Teng and Wei He (from the Nanfang Hospital in Southern Medical University) for collecting human blood samples and Xin Bin (from The Ohio State University at Columbus) for secretarial assistance. This work was supported by grants from the National Natural Science Foundation of China (81170146, to Y.L.), the Team Program of Natural Science Foundation of Guangdong Province, China (S2011030003134, to Y.L. and B.J.).

Conflict of interest

None.

Supplementary material

395_2013_342_MOESM1_ESM.ppt (2.3 mb)
Supplementary material 1 (PPT 2345 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Tao Luo
    • 1
  • Baihe Chen
    • 1
  • Zonglei Zhao
    • 1
  • Nvqin He
    • 1
  • Zhi Zeng
    • 1
  • Bing Wu
    • 1
  • Yasushi Fukushima
    • 4
  • Meng Dai
    • 5
  • Qiaobing Huang
    • 2
  • Dingli Xu
    • 1
  • Jianping Bin
    • 1
  • Masafumi Kitakaze
    • 3
  • Yulin Liao
    • 1
    Email author
  1. 1.Department of CardiologyNanfang Hospital, Southern Medical UniversityGuangzhouChina
  2. 2.Department of PathophysiologySouthern Medical UniversityGuangzhouChina
  3. 3.Cardiovascular Division of the Department of MedicineNational Cerebral and Cardiovascular CenterOsakaJapan
  4. 4.Graduate School of Medicine, Department of Internal MedicineUniversity of TokyoTokyoJapan
  5. 5.Healthcare Management CenterNanfang Hospital, Southern Medical UniversityGuangzhouChina

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