Ophiopogonin D Increases SERCA2a Interaction with Phospholamban by Promoting CYP2J3 Upregulation.

Jia Wang,Yuguang Wang,Yunxuan Ge,Yue Gao,Hongling Tan,Wei Zhou,Wenting You,Zengchun Ma,Ningning Wang,Wuquan Deng

doi:10.1155/2020/8857906

Abstract

Ophiopogonin D (OPD), a compound from the Chinese herb Radix Ophiopogonis, reportedly induces increased levels of cytochrome P450 2J3 (CYP2J3)/epoxyeicosatrienoic acids (EETs) and Ca2+ in rat cardiomyocytes. Little is known regarding the specific mechanism between CYP2J3 and Ca2+ homeostasis. Here, we investigated whether CYP2J3 is involved in the protective action of OPD on the myocardium by activating the Ca2+ homeostasis-related protein complex (SERCA2a and PLB) in H9c2 rat cardiomyoblast cells. The interaction between SERCA2a and PLB was measured using fluorescence resonance energy transfer. OPD attenuated heart failure and catalyzed the active transport of Ca2+ into the sarcoplasmic reticulum by inducing the phosphorylation of PLB and promoting the SERCA2a activity. These beneficial effects of OPD on heart failure were abolished after knockdown of CYP2J3 in a model of heart failure. Together, our results identify CYP2J3 as a critical intracellular target for OPD and unravel a mechanism of CYP2J3-dependent regulation of intracellular Ca2+.

Highlights

Cytochrome P450 2J3 (CYP2J3) is a member of the cytochrome P450 superfamily of enzymes and catalyzes many reactions involved in the metabolism of drugs and other xenobiotics
Cells were treated with different concentrations of Ophiopogonin D (OPD) (1–80 μmol/L), and the viability of H9c2 cells was detected by the Cell Counting Kit-8 (CCK-8) assay
There is no in-depth study on whether OPD can directly affect the interaction between SERCA2a and PLB, or whether CYP2J3 participates in modulating the interaction between SERCA2a with PLB remains unknown

Summary

Introduction

Cytochrome P450 2J3 (CYP2J3) is a member of the cytochrome P450 superfamily of enzymes and catalyzes many reactions involved in the metabolism of drugs and other xenobiotics. They are highly expressed in the myocardium and are involved in the metabolism of arachidonic acid (AA). EETs can maintain Ca2+ homeostasis in myocardial cells and alleviate the symptoms of heart failure in rats by upregulating the expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLB). The CYP2J3 overexpression and increased levels of EETs reportedly decrease endoplasmic reticulum (ER) stress signaling and ER stress-mediated apoptosis in rats with heart failure (HF) by maintaining the sarcoplasmic reticulum. Industry and academic researchers have extensively searched for the affinity of the regulatory interaction between SERCA2a

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