DRm217 attenuates myocardial ischemia-reperfusion injury via stabilizing plasma membrane Na+-K+-ATPase, inhibiting Na+-K+-ATPase/ROS pathway and activating PI3K/Akt and ERK1/2

Xiaofei Yan; Meng Xun; Litao Wu; Xiaojuan Du; Fujun Zhang; J Zheng

doi:10.1016/j.taap.2018.04.030

DRm217 attenuates myocardial ischemia-reperfusion injury via stabilizing plasma membrane Na⁺-K⁺-ATPase, inhibiting Na⁺-K⁺-ATPase/ROS pathway and activating PI3K/Akt and ERK1/2

Toxicol Appl Pharmacol. 2018 Jun 15:349:62-71. doi: 10.1016/j.taap.2018.04.030. Epub 2018 Apr 25.

Authors

Xiaofei Yan¹, Meng Xun², Litao Wu³, Xiaojuan Du³, Fujun Zhang³, J Zheng⁴

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, China. Electronic address: yanxiaofei@xjtu.edu.cn.
² Department of Immunology and Microbiology, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
³ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, China.
⁴ Hospital of Nephrology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

PMID: 29702141
DOI: 10.1016/j.taap.2018.04.030

Abstract

Na⁺-K⁺-ATPase has close relationship with myocardial ischemia/reperfusion (IR) injury. Activation of Na⁺-K⁺-ATPase with its DR region specific antibody produces cardioprotective effect. In this study, we aimed to explore whether DRm217, a proved DR region specific antibody, could protect myocardial cells against IR injury and uncover the mechanisms under it. By employing H9c2 myocardial cell and SD rat, we found that DRm217 protected cardiac cells against IR-induced cell injury and apoptosis. DRm217 produced protective effect via stabilizing Na⁺-K⁺-ATPase membrane expression and inhibiting Na⁺-K⁺-ATPase/Src/NADPH oxidase dependent ROS accumulation. PI3K/Akt and ERK1/2 participated in DRm217-induced cardiomyocyte survival, but not in DRm217-related ROS reduction. Therefore, DRm217 can be used as a potential cardioprotective adjuvant in myocardial IR therapy and interference of Na⁺-K⁺-ATPase/ROS pathway will be a promising modality for clinical myocardial IR therapy.

Keywords: DRm217; Ischemia-reperfusion (IR); Myocardial cells; Na(+)-K(+)-ATPase; ROS; Src.

Publication types

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

MeSH terms

Animals
Cardiotonic Agents / pharmacology*
Cell Line
Cell Membrane / drug effects
Cell Membrane / enzymology*
Cell Survival / drug effects
Humans
MAP Kinase Signaling System / drug effects*
Male
Metabolic Networks and Pathways / drug effects*
Myocardial Reperfusion Injury / drug therapy*
Myocytes, Cardiac / drug effects
Oncogene Protein v-akt / metabolism*
Phosphatidylinositol 3-Kinases / metabolism*
Rats
Rats, Sprague-Dawley
Reactive Nitrogen Species / metabolism*
Sodium-Potassium-Exchanging ATPase / metabolism*

Substances

Cardiotonic Agents
Reactive Nitrogen Species
Oncogene Protein v-akt
Sodium-Potassium-Exchanging ATPase