Transient receptor potential melastatin-4 is involved in hypoxia-reoxygenation injury in the cardiomyocytes

Hulin Piao; Ken Takahashi; Yohei Yamaguchi; Chen Wang; Kexiang Liu; Keiji Naruse

doi:10.1371/journal.pone.0121703

Transient receptor potential melastatin-4 is involved in hypoxia-reoxygenation injury in the cardiomyocytes

PLoS One. 2015 Apr 2;10(4):e0121703. doi: 10.1371/journal.pone.0121703. eCollection 2015.

Authors

Hulin Piao¹, Ken Takahashi², Yohei Yamaguchi², Chen Wang³, Kexiang Liu⁴, Keiji Naruse²

Affiliations

¹ Department of Cardiovascular Surgery, the Second Affiliated Hospital of Jilin University, Changchun, China; Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
² Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
³ Department of Cardiology, Graduate School, Dalian Medical University, Dalian, China.
⁴ Department of Cardiovascular Surgery, the Second Affiliated Hospital of Jilin University, Changchun, China.

Abstract

Ischemic heart disease still remains the most common cause of cardiac death. During ischemia-reperfusion (I/R), reactive oxygen species (ROS) are produced in excess in cardiac tissue, where they induce cell death. Our previous study showed that 9-phenanthrol (9-Phe), a specific inhibitor of the TRPM4 channel, preserves cardiac contractile function and protects the heart from I/R injury-related infarction in the excised rat heart. Accordingly, we hypothesized that TRPM4 channels are involved in the 9-Phe-mediated cardioprotection against ROS-induced injury. In rats, intravenous 9-Phe mitigated the development of myocardial infarction caused by the occlusion of the left anterior descending artery. Immunohistochemical analysis indicated that TRPM4 proteins are expressed in ventricular myocytes susceptible to I/R injury. Hydrogen peroxide (H2O2) is among the main ROS overproduced during I/R. In the cardiomyocyte cell line H9c2, pretreatment with 9-Phe prevented cell death induced by conditions mimicking I/R, namely 200 μM H2O2 and hypoxia-reoxygenation. Gene silencing of TRPM4 preserved the viability of H9c2 cardiomyocytes exposed to 200 μM H2O2. These results suggest that the cardioprotective effects of 9-Phe are mediated through the inhibition of the TRPM4 channels.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiotonic Agents / pharmacology*
Cell Line
Cerebrovascular Disorders / drug therapy*
Cerebrovascular Disorders / genetics
Cerebrovascular Disorders / metabolism
Cerebrovascular Disorders / pathology
Gene Expression
Hydrogen Peroxide / metabolism
Hydrogen Peroxide / pharmacology
Ion Transport / drug effects
Ischemic Preconditioning, Myocardial
Male
Myocardial Contraction / drug effects
Myocardial Reperfusion Injury / genetics
Myocardial Reperfusion Injury / metabolism
Myocardial Reperfusion Injury / pathology
Myocardial Reperfusion Injury / prevention & control*
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology
Organ Culture Techniques
Phenanthrenes / pharmacology*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Rats
Rats, Sprague-Dawley
TRPM Cation Channels / antagonists & inhibitors
TRPM Cation Channels / genetics*
TRPM Cation Channels / metabolism

Substances

Cardiotonic Agents
Phenanthrenes
RNA, Small Interfering
TRPM Cation Channels
TRPM4 protein, rat
9-phenanthrol
Hydrogen Peroxide

Grants and funding

The work of Hulin Piao was supported by a scholarship from the China Scholarship Council. This work was funded by a Grant-in-Aid for Strategic Research Promotion by the Okayama University.